Donors, Acceptors, and Traps in AlGaN and AlGaN/GaN Epitaxial Layers

DTIC Science & Technology

2006-07-31

the background. 3.3 Positron annihilation spectroscopy (PAS): acceptor-type defects Positrons injected into defect-free GaN are annihilated by electrons...electron concentration n, and the average Ga-vacancy VGa concentration deduced from positron annihilation spectroscopy . 0.09 3.47 3.46 - 3.45 •ŗ.47225...of this paper, are often investigated by deep level transient spectroscopy (DLTS), and the usual analysis of DLTS data is based on the assumption that

Admittance spectroscopy or deep level transient spectroscopy: A contrasting juxtaposition

NASA Astrophysics Data System (ADS)

Bollmann, Joachim; Venter, Andre

2018-04-01

A comprehensive understanding of defects in semiconductors remains of primary importance. In this paper the effectiveness of two of the most commonly used semiconductor defect spectroscopy techniques, viz. deep level transient spectroscopy (DLTS) and admittance spectroscopy (AS) are reviewed. The analysis of defects present in commercially available SiC diodes shows that admittance spectroscopy allows the identification of deep traps with reduced measurement effort compared to deep Level Transient Spectroscopy (DLTS). Besides the N-donor, well-studied intrinsic defects were detected in these diodes. Determination of their activation energy and defect density, using the two techniques, confirm that the sensitivity of AS is comparable to that of DLTS while, due to its well defined peak shape, the spectroscopic resolution is superior. Additionally, admittance spectroscopy can analyze faster emission processes which make the study of shallow defects more practical and even that of shallow dopant levels, possible. A comparative summary for the relevant spectroscopic features of the two capacitance methods are presented.

Tutorial: Junction spectroscopy techniques and deep-level defects in semiconductors

NASA Astrophysics Data System (ADS)

Peaker, A. R.; Markevich, V. P.; Coutinho, J.

2018-04-01

The term junction spectroscopy embraces a wide range of techniques used to explore the properties of semiconductor materials and semiconductor devices. In this tutorial review, we describe the most widely used junction spectroscopy approaches for characterizing deep-level defects in semiconductors and present some of the early work on which the principles of today's methodology are based. We outline ab-initio calculations of defect properties and give examples of how density functional theory in conjunction with formation energy and marker methods can be used to guide the interpretation of experimental results. We review recombination, generation, and trapping of charge carriers associated with defects. We consider thermally driven emission and capture and describe the techniques of Deep Level Transient Spectroscopy (DLTS), high resolution Laplace DLTS, admittance spectroscopy, and scanning DLTS. For the study of minority carrier related processes and wide gap materials, we consider Minority Carrier Transient Spectroscopy (MCTS), Optical DLTS, and deep level optical transient spectroscopy together with some of their many variants. Capacitance, current, and conductance measurements enable carrier exchange processes associated with the defects to be detected. We explain how these methods are used in order to understand the behaviour of point defects and the determination of charge states and negative-U (Hubbard correlation energy) behaviour. We provide, or reference, examples from a wide range of materials including Si, SiGe, GaAs, GaP, GaN, InGaN, InAlN, and ZnO.

Deep levels in H-irradiated GaAs1-xNx (x < 0.01) grown by molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Shafi, M.; Mari, R. H.; Khatab, A.; Henini, M.; Polimeni, A.; Capizzi, M.; Hopkinson, M.

2011-12-01

Dilute nitride GaAs1-xNx layers have been grown by molecular beam epitaxy with nitrogen concentration ranging from 0.2% to 0.8%. These samples have been studied before and after hydrogen irradiation by using standard deep level transient spectroscopy (DLTS) and high resolution Laplace DLTS techniques. The activation energy, capture cross section and density of the electron traps have been estimated and compared with results obtained in N-free as-grown and H-irradiated bulk GaAs.

Deep level transient spectroscopy signatures of majority traps in GaN p-n diodes grown by metal-organic vapor-phase epitaxy technique on GaN substrates

NASA Astrophysics Data System (ADS)

PŁaczek-Popko, E.; Trzmiel, J.; Zielony, E.; Grzanka, S.; Czernecki, R.; Suski, T.

2009-12-01

In this study, we present the results of investigation on p-n GaN diodes by means of deep level transient spectroscopy (DLTS) within the temperature range of 77-350 K. Si-doped GaN layers were grown by metal-organic vapor-phase epitaxy technique (MOVPE) on the free-standing GaN substrates. Subsequently Mg-doped GaN layers were grown. To perform DLTS measurements Ni/Au contacts to p-type material and Ti/Au contacts to n-type material were processed. DLTS signal spectra revealed the presence of two majority traps of activation energies obtained from Arrhenius plots equal to E1=0.22 eV and E2=0.65 eV. In present work we show that the trap E1 is linked with the extended defects whereas the trap E2 is the point defect related. Its capture cross section is thermally activated with energy barrier for capture equal to 0.2 eV.

Characterisation of Cs ion implanted GaN by DLTS

NASA Astrophysics Data System (ADS)

Ngoepe, P. N. M.; Meyer, W. E.; Auret, F. D.; Omotoso, E.; Hlatshwayo, T. T.; Diale, M.

2018-04-01

Deep level transient spectroscopy (DLTS) was used to characterise Cs implanted GaN grown by hydride vapour phase epitaxy (HVPE). This implantation was done at room temperature using energy of 360 keV to a fluence of 10-11 cm-2. A defect with activation energy of 0.19 eV below the conduction band and an apparent capture cross section of 1.1 × 10-15 cm2 was induced. This defect has previously been observed after rare earth element (Eu, Er and Pr) implantation. It has also been reported after electron, proton and He ion implantation.

Computed Tomographic Window Setting for Bronchial Measurement to Guide Double-Lumen Tube Size.

PubMed

Seo, Jeong-Hwa; Bae, Jinyoung; Paik, Hyesun; Koo, Chang-Hoon; Bahk, Jae-Hyon

2018-04-01

The bronchial diameter measured on computed tomography (CT) can be used to guide double-lumen tube (DLT) sizes objectively. The bronchus is known to be measured most accurately in the so-called bronchial CT window. The authors investigated whether using the bronchial window results in the selection of more appropriately sized DLTs than using the other windows. CT image analysis and prospective randomized study. Tertiary hospital. Adults receiving left-sided DLTs. The authors simulated selection of DLT sizes based on the left bronchial diameters measured in the lung (width 1,500 Hounsfield unit [HU] and level -700 HU), bronchial (1,000 HU and -450 HU), and mediastinal (400 HU and 25 HU) CT windows. Furthermore, patients were randomly assigned to undergo imaging with either the bronchial or mediastinal window to guide DLT sizes. Using the underwater seal technique, the authors assessed whether the DLT was appropriately sized, undersized, or oversized for the patient. On 130 CT images, the bronchial diameter (9.9 ± 1.2 mm v 10.5 ± 1.3 mm v 11.7 ± 1.3 mm) and the selected DLT size were different in the lung, bronchial, and mediastinal windows, respectively (p < 0.001). In 13 patients (17%), the bronchial diameter measured in the lung window suggested too small DLTs (28 Fr) for adults. In the prospective study, oversized tubes were chosen less frequently in the bronchial window than in the mediastinal window (6/110 v 23/111; risk ratio 0.38; 95% CI 0.19-0.79; p = 0.003). No tubes were undersized after measurements in these two windows. The bronchial measurement in the bronchial window guided more appropriately sized DLTs compared with the lung or mediastinal windows. Copyright © 2017 Elsevier Inc. All rights reserved.

Deep traps in n-type GaN epilayers grown by plasma assisted molecular beam epitaxy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamyczek, P.; Placzek-Popko, E.; Zielony, E.

2014-01-14

In this study, we present the results of investigations on Schottky Au-GaN diodes by means of conventional DLTS and Laplace DLTS methods within the temperature range of 77 K–350 K. Undoped GaN layers were grown using the plasma-assisted molecular beam epitaxy technique on commercial GaN/sapphire templates. The quality of the epilayers was studied by micro-Raman spectroscopy (μ-RS) which proved the hexagonal phase and good crystallinity of GaN epilayers as well as a slight strain. The photoluminescence spectrum confirmed a high crystal quality by intense excitonic emission but it also exhibited a blue emission band of low intensity. DLTS signal spectra revealed themore » presence of four majority traps: two high-temperature and two low-temperature peaks. Using the Laplace DLTS method and Arrhenius plots, the apparent activation energy and capture cross sections were obtained. For two high-temperature majority traps, they were equal to E{sub 1} = 0.65 eV, σ{sub 1} = 8.2 × 10{sup −16} cm{sup 2} and E{sub 2} = 0.58 eV, σ{sub 2} = 2.6 × 10{sup −15} cm{sup 2} whereas for the two low-temperature majority traps they were equal to E{sub 3} = 0.18 eV, σ{sub 3} = 9.7 × 10{sup −18} cm{sup 2} and E{sub 4} = 0.13 eV, σ{sub 4} = 9.2 × 10{sup −18} cm{sup 2}. The possible origin of the traps is discussed and the results are compared with data reported elsewhere.« less

Carrier removal and defect behavior in p-type InP

NASA Technical Reports Server (NTRS)

Weinberg, I.; Swartz, C. K.; Drevinsky, P. J.

1992-01-01

A simple expression, obtained from the rate equation for defect production, was used to relate carrier removal to defect production and hole trapping rates in p-type InP after irradiation by 1-MeV electrons. Specific contributions to carrier removal from defect levels H3, H4, and H5 were determined from combined deep-level transient spectroscopy (DLTS) and measured carrier concentrations. An additional contribution was attributed to one or more defects not observed by the present DLTS measurements. The high trapping rate observed for H5 suggests that this defect, if present in relatively high concentration, could be dominant in p-type InP.

Hole defects in molecular beam epitaxially grown p-GaAs introduced by alpha irradiation

NASA Astrophysics Data System (ADS)

Goodman, S. A.; Auret, F. D.; Meyer, W. E.

1994-01-01

Epitaxial aluminum Schottky barrier diodes on molecular beam epitaxially grown p-GaAs with a free carrier density of 2×1016 cm-3 were irradiated with alpha particles at room temperature using an americium-241 (Am-241) radio nuclide. For the first time, the radiation induced hole defects are characterized using conventional deep level transient spectroscopy (DLTS). The introduction rates and DLTS ``signatures'' of three prominent radiation induced defects Hα1, Hα4, and Hα5, situated 0.08, 0.20, and 0.30 eV above the valence band, respectively, are calculated and compared to those of similar defects introduced during electron irradiation.

Charge Trapping Properties of Ge Nanocrystals Grown via Solid-State Dewetting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, Steven; Jadli, I.; Aouassa, M.

2018-05-04

In the present work, we report on the charge trapping properties of Germanium Nanocrystals (Ge NCs) self assembled on SiO2 thin layer for promising applications in next-generation non volatile memory by the means of Deep Level Transient Spectroscopy (DLTS) and high frequency C-V method. The Ge NCs were grown via dewetting phenomenon at solid state by Ultra-High Vacuum (UHV) annealing and passivated with silicon before SiO2 capping. The role of the surface passivation is to reduce the electrical defect density at the Ge NCs-SiO2 interface. The presence of the Ge NCs in the oxide of the MOS capacitors strongly affectsmore » the C-V characteristics and increases the accumulation capacitance, causes a negative flat band voltage (VFB) shift. The DLTS has been used to study the individual Ge NCs as a single point deep level defect in the oxide. DLTS reveals two main features: the first electron traps around 255 K could correspond to dangling bonds at the Si/SiO2 interface and the second, at high-temperature (>300 K) response, could be originated from minority carrier generation in Ge NCs.« less

Deep level transient spectroscopy (DLTS) on colloidal-synthesized nanocrystal solids.

PubMed

Bozyigit, Deniz; Jakob, Michael; Yarema, Olesya; Wood, Vanessa

2013-04-24

We demonstrate current-based, deep level transient spectroscopy (DLTS) on semiconductor nanocrystal solids to obtain quantitative information on deep-lying trap states, which play an important role in the electronic transport properties of these novel solids and impact optoelectronic device performance. Here, we apply this purely electrical measurement to an ethanedithiol-treated, PbS nanocrystal solid and find a deep trap with an activation energy of 0.40 eV and a density of NT = 1.7 × 10(17) cm(-3). We use these findings to draw and interpret band structure models to gain insight into charge transport in PbS nanocrystal solids and the operation of PbS nanocrystal-based solar cells.

Capacitance spectroscopy on n-type GaNAs/GaAs embedded quantum structure solar cells

NASA Astrophysics Data System (ADS)

Venter, Danielle; Bollmann, Joachim; Elborg, Martin; Botha, J. R.; Venter, André

2018-04-01

In this study, both deep level transient spectroscopy (DLTS) and admittance spectroscopy (AS) have been used to study the properties of electrically active deep level centers present in GaNAs/GaAs quantum wells (QWs) embedded in p-i-n solar cells. The structures were grown by molecular beam epitaxy (MBE). In particular, the electrical properties of samples with Si (n-type) doping of the QWs were investigated. DLTS revealed four deep level centers in the material, whereas only three were detected by AS. NextNano++ simulation software was used to model the sample band-diagrams to provide reasoning for the origin of the signals produced by both techniques.

Investigation of defect properties in Cu(In,Ga)Se 2 solar cells by deep-level transient spectroscopy

NASA Astrophysics Data System (ADS)

Kerr, L. L.; Li, Sheng S.; Johnston, S. W.; Anderson, T. J.; Crisalle, O. D.; Kim, W. K.; Abushama, J.; Noufi, R. N.

2004-09-01

The performance of the chalcopyrite material Cu(In,Ga)Se 2 (CIGS) used as an absorber layer in thin-film photovoltaic devices is significantly affected by the presence of native defects. The deep-level transient spectroscopy (DLTS) technique is used in this work to characterize the defect properties, yielding relevant information about the defect types, their capture cross-sections, and energy levels and densities in the CIGS cells. Three solar cells developed using different absorber growth technologies were analyzed using DLTS, capacitance-voltage ( C- V), and capacitance-temperature ( C- T) techniques. It was found that CIS cells grown at the University of Florida exhibits a middle-gap defect level that may relate to the cell's low fill factor and open-circuit voltage values observed. A high efficiency ( ηc>18%) CIGS cell produced by the National Renewable Energy Laboratory (NREL) was found to contain three minority-carrier (electron) traps and a 13% CIGS cell produced by the Energy Photovoltaics Inc. (EPV) exhibited one majority (hole) trap. The approach followed using the DLTS technique serves as a paradigm for revealing the presence of significant defect levels in absorber materials, and may be used to support the identification of remedial processing operations.

Annealing behavior of the EB-centers and M-center in low-energy electron irradiated n-type 4H-SiC

NASA Astrophysics Data System (ADS)

Beyer, F. C.; Hemmingsson, C.; Pedersen, H.; Henry, A.; Janzén, E.; Isoya, J.; Morishita, N.; Ohshima, T.

2011-05-01

After low-energy electron irradiation of epitaxial n-type 4H-SiC with a dose of 5×1016 cm-2, the bistable M-center, previously reported in high-energy proton implanted 4H-SiC, is detected in the deep level transient spectroscopy (DLTS) spectrum. The annealing behavior of the M-center is confirmed, and an enhanced recombination process is suggested. The annihilation process is coincidental with the evolvement of the bistable EB-centers in the low temperature range of the DLTS spectrum. The annealing energy of the M-center is similar to the generation energy of the EB-centers, thus partial transformation of the M-center to the EB-centers is suggested. The EB-centers completely disappeared after annealing temperatures higher than 700 ∘C without the formation of new defects in the observed DLTS scanning range. The threshold energy for moving Si atom in SiC is higher than the applied irradiation energy, and the annihilation temperatures are relatively low, therefore the M-center, EH1 and EH3, as well as the EB-centers are attributed to defects related to the C atom in SiC, most probably to carbon interstitials and their complexes.

Direct observation of 0.57 eV trap-related RF output power reduction in AlGaN/GaN high electron mobility transistors

NASA Astrophysics Data System (ADS)

Arehart, A. R.; Sasikumar, A.; Rajan, S.; Via, G. D.; Poling, B.; Winningham, B.; Heller, E. R.; Brown, D.; Pei, Y.; Recht, F.; Mishra, U. K.; Ringel, S. A.

2013-02-01

This paper reports direct evidence for trap-related RF output power loss in GaN high electron mobility transistors (HEMTs) grown by metal organic chemical vapor deposition (MOCVD) through increased concentration of a specific electron trap at EC-0.57 eV that is located in the drain access region, as a function of accelerated life testing (ALT). The trap is detected by constant drain current deep level transient spectroscopy (CID-DLTS) and the CID-DLTS thermal emission time constant precisely matches the measured drain lag. Both drain lag and CID-DLTS measurements show this state to already exist in pre-stressed devices, which coupled with its strong increase in concentration as a function of stress in the absence of significant increases in concentrations of other detected traps, imply its role in causing degradation, in particular knee walkout. This study reveals EC-0.57 eV trap concentration tracks degradation induced by ALT for MOCVD-grown HEMTs supplied by several commercial and university sources. The results suggest this defect has a common source and may be a key degradation pathway in AlGaN/GaN HEMTs and/or an indicator to predict device lifetime.

Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.

PubMed

Lewin, Jeremy; Soria, Jean-Charles; Stathis, Anastasios; Delord, Jean-Pierre; Peters, Solange; Awada, Ahmad; Aftimos, Philippe G; Bekradda, Mohamed; Rezai, Keyvan; Zeng, Zhen; Hussain, Azher; Perez, Susan; Siu, Lillian L; Massard, Christophe

2018-05-07

Purpose Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. Patients and Methods Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose. Results Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption. Conclusion The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.

Effect of gamma-ray irradiation on the device process-induced defects in 4H-SiC epilayers

NASA Astrophysics Data System (ADS)

Miyazaki, T.; Makino, T.; Takeyama, A.; Onoda, S.; Ohshima, T.; Tanaka, Y.; Kandori, M.; Yoshie, T.; Hijikata, Y.

2016-11-01

We investigated the gamma-ray irradiation effect on 4H-SiC device process-induced defects by photoluminescence (PL) imaging and deep level transient spectroscopy (DLTS). We found that basal plane dislocations (BPDs) that were present before the irradiation were eliminated by gamma-ray irradiation of 1 MGy. The reduction mechanism of BPD was discussed in terms of BPD-threading edge dislocation (TED) transformation and shrinkage of stacking faults. In addition, the entire PL image was gradually darkened with increasing absorbed dose, which is presumably due to the point defects generated by gamma-ray irradiation. We obtained DLTS peaks that could be assigned to complex defects, termed RD series, and found that the peaks increased with absorbed dose.

Impact of the silicon substrate resistivity and growth condition on the deep levels in Ni-Au/AlN/Si MIS Capacitors

NASA Astrophysics Data System (ADS)

Wang, Chong; Simoen, Eddy; Zhao, Ming; Li, Wei

2017-10-01

Deep levels formed under different growth conditions of a 200 nm AlN buffer layer on B-doped Czochralski Si(111) substrates with different resistivity were investigated by deep-level transient spectroscopy (DLTS) on metal-insulator-semiconductor capacitors. Growth-temperature-dependent Al diffusion in the Si substrate was derived from the free carrier density obtained by capacitance-voltage measurement on samples grown on p- substrates. The DLTS spectra revealed a high concentration of point and extended defects in the p- and p+ silicon substrates, respectively. This indicated a difference in the electrically active defects in the silicon substrate close to the AlN/Si interface, depending on the B doping concentration.

Influence of surface pre-treatment on the electronic levels in silicon MaWCE nanowires.

PubMed

Venturi, Giulia; Castaldini, Antonio; Schleusener, Alexander; Sivakov, Vladimir; Cavallini, Anna

2015-05-15

Deep level transient spectroscopy (DLTS) was performed on n-doped silicon nanowires grown by metal-assisted wet chemical etching (MaWCE) with gold as the catalyst in order to investigate the energetic scheme inside the bandgap. To observe the possible dependence of the level scheme on the processing temperature, DLTS measurements were performed on the nanowires grown on a non-treated Au/Si surface and on a thermally pre-treated Au/Si surface. A noticeable modification of the configuration of the energy levels was observed, induced by the annealing process. Based on our results on these MaWCE nanowires and on literature data about deep levels in bulk silicon, some hypotheses were advanced regarding the identification of the defects responsible of the energy levels revealed.

Impact of strain on electronic defects in (Mg,Zn)O thin films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmidt, Florian, E-mail: fschmidt@physik.uni-leipzig.de; Müller, Stefan; Wenckstern, Holger von

2014-09-14

We have investigated the impact of strain on the incorporation and the properties of extended and point defects in (Mg,Zn)O thin films by means of photoluminescence, X-ray diffraction, deep-level transient spectroscopy (DLTS), and deep-level optical spectroscopy. The recombination line Y₂, previously detected in ZnO thin films grown on an Al-doped ZnO buffer layer and attributed to tensile strain, was exclusively found in (Mg,Zn)O samples being under tensile strain and is absent in relaxed or compressively strained thin films. Furthermore a structural defect E3´ can be detected via DLTS measurements and is only incorporated in tensile strained samples. Finally it ismore » shown that the omnipresent deep-level E3 in ZnO can only be optically recharged in relaxed ZnO samples.« less

DLTS analysis of radiation-induced defects in one-MeV electron irradiated germanium and Alsub0.17Gasub0.83As solar cells

NASA Technical Reports Server (NTRS)

Li, S. B.; Choi, C. G.; Loo, R. Y.

1985-01-01

The radiation-induced deep-level defects in one-MeV electron-irradiated germanium and AlxGal-xAs solar cell materials using the deep-level transient spectroscopy (DLTS) and C-V techniques were investigated. Defect and recombination parameters such as defect density and energy levels, capture cross sections and lifetimes for both electron and hole traps were determined. The germanium and AlGaAs p/n junction cells were irradiated by one-MeV electrons. The DLTS, I-V, and C-V measurements were performed on these cells. The results are summarized as follows: (1) for the irradiated germanium samples, the dominant electron trap was due to the E sub - 0.24 eV level with density around 4x10 to the 14th power 1/cu cm, independent of electron fluence, its origin is attributed to the vacancy-donor complex defect formed during the electron irradiation; (2) in the one-MeV electron irradiated Al0.17Ga0.83 as sample, two dominant electron traps with energies of Ec-0.19 and -0.29 eV were observed, the density for both electron traps remained nearly constant, independent of electron fluence. It is shown that one-MeV electron irradiation creates very few or no new deep-level traps in both the germanium and AlxGa1-xAs cells, and are suitable for fabricating the radiation-hard high efficiency multijunction solar cells for space applications.

Identification of dopant-induced point defects and their effect on the performance of CZT detectors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Gul, Rubi; Bolotnikov, Aleksey E.; Camarda, Giuseppe S.; Cui, Yonggang; Didic, Václav; Egarievwe, Stephen U.; Hossain, Anwar; Roy, Utpal N.; Yang, Ge; James, Ralph B.

2016-09-01

In our prior research we investigated room-temperature radiation detectors (CZT, CMT, CdMgTe, CTS, among other compound semiconductors) for point defects related to different dopants and impurities. In this talk we will report on our most recent research on newly grown CZT crystals doped with In, In+Al, In+Ni, and In+Sn. The main focus will be on the study of dopant-induced point defects using deep-level current transient spectroscopy (i-DLTS). In addition the performance, ? product, gamma-ray spectral response and internal electric field of the detectors were measured and correlated with the dopant-induced point defects and their concentrations. Characterization of the detectors was carried out using i-DLTS for the point defects, Pockels effect for the internal electric-field distribution, and γ-ray spectroscopy for the spectral properties.

Electrically active defects in p-type silicon after alpha-particle irradiation

NASA Astrophysics Data System (ADS)

Danga, Helga T.; Auret, F. Danie; Tunhuma, Shandirai M.; Omotoso, Ezekiel; Igumbor, Emmanuel; Meyer, Walter E.

2018-04-01

In this work, we investigated the defects introduced when boron (B) doped silicon (Si) was irradiated by making use of a 5.4 MeV americium (Am) 241 foil radioactive source with a fluence rate of 7×106 cm-2 s-1 at room temperature. Deep level transient spectroscopy (DLTS) and Laplace-DLTS measurements were used to investigate the electronic properties of the introduced defects. After exposure at a fluence of 5.1×1010 cm-2, the energy levels of the hole traps measured were: H(0.10), H(0.16), H(0.33) and H(0.52) The defect level H(0.10) was tri-vacancy related. H(0.33) was identified as the interstitial carbon (Ci) related defect which was a result of radiation induced damage. H(0.52) was a B-related defect. Explicit deductions about the origin of H(0.16) have not yet been achieved.

Comparison and Interpretation of Admittance Spectroscopy and Deep Level Transient Spectroscopy from Co-Evaporated and Solution-Deposited Cu2ZnSn(Sx, Se1-x)4 Solar Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caruso, A. E.; Lund, E. A.; Kosyak, V.

2016-11-21

Cu2ZnSn(S, Se)4 (CZTSe) is an earth-abundant semiconductor with potential for economical thin-film photovoltaic devices. Short minority carrier lifetimes contribute to low open circuit voltage and efficiency. Deep level defects that may contribute to lower minority carrier lifetimes in kesterites have been theoretically predicted, however very little experimental characterization of these deep defects exists. In this work we use admittance spectroscopy (AS) and deep level transient spectroscopy (DLTS) to characterize devices built using CZTSSe absorber layers deposited via both coevaporation and solution processing. AS reveals a band of widely-distributed activation energies for traps or energy barriers for transport, especially in themore » solution deposited case. DLTS reveals signatures of deep majority and minority traps within both types of samples.« less

Radiation damage and defect behavior in ion-implanted, lithium counterdoped silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Mehta, S.; Swartz, C. K.

1984-01-01

Boron doped silicon n+p solar cells were counterdoped with lithium by ion implantation and the resuitant n+p cells irradiated by 1 MeV electrons. The function of fluence and a Deep Level Transient Spectroscopy (DLTS) was studied to correlate defect behavior with cell performance. It was found that the lithium counterdoped cells exhibited significantly increased radiation resistance when compared to boron doped control cells. It is concluded that the annealing behavior is controlled by dissociation and recombination of defects. The DLTS studies show that counterdoping with lithium eliminates at least three deep level defects and results in three new defects. It is speculated that the increased radiation resistance of the counterdoped cells is due primarily to the interaction of lithium with oxygen, single vacanies and divacancies and that the lithium-oxygen interaction is the most effective in contributing to the increased radiation resistance.

Radiation damage and defect behavior in ion-implanted, lithium counterdoped silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Mehta, S.; Swartz, C. K.

1984-01-01

Boron doped silicon n+p solar cells were counterdoped with lithium by ion implanation and the resultant n+p cells irradiated by 1 MeV electrons. The function of fluence and a Deep Level Transient Spectroscopy (DLTS) was studied to correlate defect behavior with cell performance. It was found that the lithium counterdoped cells exhibited significantly increased radiation resistance when compared to boron doped control cells. It is concluded that the annealing behavior is controlled by dissociation and recombination of defects. The DLTS studies show that counterdoping with lithium eliminates at least three deep level defects and results in three new defects. It is speculated that the increased radiation resistance of the counterdoped cells is due primarily to the interaction of lithium with oxygen, single vacancies and divacancies and that the lithium-oxygen interaction is the most effective in contributing to the increased radiation resistance.

Deep level transient spectroscopic analysis of p/n junction implanted with boron in n-type silicon substrate

NASA Astrophysics Data System (ADS)

Wakimoto, Hiroki; Nakazawa, Haruo; Matsumoto, Takashi; Nabetani, Yoichi

2018-04-01

For P-i-N diodes implanted and activated with boron ions into a highly-resistive n-type Si substrate, it is found that there is a large difference in the leakage current between relatively low temperature furnace annealing (FA) and high temperature laser annealing (LA) for activation of the p-layer. Since electron trap levels in the n-type Si substrate is supposed to be affected, we report on Deep Level Transient Spectroscopy (DLTS) measurement results investigating what kinds of trap levels are formed. As a result, three kinds of electron trap levels are confirmed in the region of 1-4 μm from the p-n junction. Each DLTS peak intensity of the LA sample is smaller than that of the FA sample. In particular, with respect to the trap level which is the closest to the silicon band gap center most affecting the reverse leakage current, it was not detected in LA. It is considered that the electron trap levels are decreased due to the thermal energy of LA. On the other hand, four kinds of trap levels are confirmed in the region of 38-44 μm from the p-n junction and the DLTS peak intensities of FA and LA are almost the same, considering that the thermal energy of LA has not reached this area. The large difference between the reverse leakage current of FA and LA is considered to be affected by the deep trap level estimated to be the interstitial boron.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

PubMed Central

2013-01-01

Background Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Methods Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Results Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0–t were dose proportional for the 6–12 mg/m2 doses. Conclusion The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. Trial registration The study was registered with ClinicalTrials.gov as NCT01755390. PMID:24099585

Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy.

PubMed

Ishihara, Hiroki; Takagi, Toshio; Kondo, Tsunenori; Tachibana, Hidekazu; Yoshida, Kazuhiko; Omae, Kenji; Iizuka, Junpei; Kobayashi, Hirohito; Tanabe, Kazunari

2018-06-01

The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited. The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy. In addition, dose-limiting toxicities (DLTs) were evaluated. Twenty-two of 48 patients (45.8%) received third-line therapy, and TKI and mammalian target of rapamycin inhibitor were each administered in 11 patients (50%). Patients with third-line therapy had significantly longer median OS after first-line therapy (26.6 vs. 14.6 months, p = 0.0010) and second-line therapy (18.2 vs. 7.4 months, p < 0.0001) compared to those without third-line therapy. Multivariate analysis showed that the use of third-line therapy following second-line therapy was an independent prognosticator for longer OS (hazard ratio 0.29, 95% confidence interval 0.14-0.58, p = 0.0005). The median progression-free survival and OS after third-line therapy was 2.76 and 8.71 months, respectively. Although a high frequency of DLTs was observed (n = 10, 45.5%), the frequencies were similar among the sequential therapies. Third-line therapy has a beneficial therapeutic effect in patients with mRCC that is resistant to previous therapies. However, there is a need to evaluate in detail the high frequency of adverse events, including DLTs.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

PubMed

Bautista, Francisco; Moreno, Lucas; Marshall, Lynley; Pearson, Andrew D J; Geoerger, Birgit; Paoletti, Xavier

2017-11-01

Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Deep level defects in Ge-doped (010) β-Ga2O3 layers grown by plasma-assisted molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Farzana, Esmat; Ahmadi, Elaheh; Speck, James S.; Arehart, Aaron R.; Ringel, Steven A.

2018-04-01

Deep level defects were characterized in Ge-doped (010) β-Ga2O3 layers grown by plasma-assisted molecular beam epitaxy (PAMBE) using deep level optical spectroscopy (DLOS) and deep level transient (thermal) spectroscopy (DLTS) applied to Ni/β-Ga2O3:Ge (010) Schottky diodes that displayed Schottky barrier heights of 1.50 eV. DLOS revealed states at EC - 2.00 eV, EC - 3.25 eV, and EC - 4.37 eV with concentrations on the order of 1016 cm-3, and a lower concentration level at EC - 1.27 eV. In contrast to these states within the middle and lower parts of the bandgap probed by DLOS, DLTS measurements revealed much lower concentrations of states within the upper bandgap region at EC - 0.1 - 0.2 eV and EC - 0.98 eV. There was no evidence of the commonly observed trap state at ˜EC - 0.82 eV that has been reported to dominate the DLTS spectrum in substrate materials synthesized by melt-based growth methods such as edge defined film fed growth (EFG) and Czochralski methods [Zhang et al., Appl. Phys. Lett. 108, 052105 (2016) and Irmscher et al., J. Appl. Phys. 110, 063720 (2011)]. This strong sensitivity of defect incorporation on crystal growth method and conditions is unsurprising, which for PAMBE-grown β-Ga2O3:Ge manifests as a relatively "clean" upper part of the bandgap. However, the states at ˜EC - 0.98 eV, EC - 2.00 eV, and EC - 4.37 eV are reminiscent of similar findings from these earlier results on EFG-grown materials, suggesting that possible common sources might also be present irrespective of growth method.

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer.

PubMed

Daga, Haruko; Takeda, Koji; Okada, Hideaki; Miyazaki, Masaki; Ueda, Shinya; Kaneda, Hiroyasu; Okamoto, Isamu; Yoh, Kiyotaka; Goto, Koichi; Konishi, Koichi; Sarashina, Akiko; Tanaka, Tetsuya; Kaiser, Rolf; Nakagawa, Kazuhiko

2015-12-01

This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.

Modeling of asymmetric degradation based on a non-uniform electric field and temperature in amorphous In-Ga-Zn-O thin film transistors

NASA Astrophysics Data System (ADS)

In Kim, Jong; Jeong, Chan-Yong; Kwon, Hyuck-In; Jung, Keum Dong; Park, Mun Soo; Kim, Ki Hwan; Seo, Mi Seon; Lee, Jong-Ho

2017-03-01

We propose a new local degradation model based on a non-uniform increase in donor-like traps (DLTs) determined by distributions of an electric field and measured device temperature in amorphous In-Ga-Zn-O (a-IGZO) thin film transistors (TFTs). A systematic investigation of the degradation model reveals that vertical field-dependent DLTs are essential for modeling of measured asymmetric electrical characteristics between the source and drain after positive gate and drain bias stressing. An increased temperature due to self-heating is found to play a role in intensifying the asymmetric degradation. From the individual simulation of measured transfer curves at different stress times, the model parameters and an asymmetry index as a function of stress time are extracted. It is expected that this novel methodology will provide new insight into asymmetric degradation and be utilized to predict the influence of electric field and heat on degradation under various bias-stress conditions in a-IGZO TFTs.

Injection deep level transient spectroscopy: An improved method for measuring capture rates of hot carriers in semiconductors

DOE PAGES

Fleming, R. M.; Seager, C. H.; Lang, D. V.; ...

2015-07-02

In this study, an improved method for measuring the cross sections for carrier trapping at defects in semiconductors is described. This method, a variation of deep level transient spectroscopy(DLTS) used with bipolar transistors, is applied to hot carrier trapping at vacancy-oxygen, carbon-oxygen, and three charge states of divacancy centers (V 2) in n- and p-type silicon. Unlike standard DLTS, we fill traps by injecting carriers into the depletion region of a bipolar transistor diode using a pulse of forward bias current applied to the adjacent diode. We show that this technique is capable of accurately measuring a wide range ofmore » capture cross sections at varying electric fields due to the control of the carrier density it provides. Because this technique can be applied to a variety of carrier energy distributions, it should be valuable in modeling the effect of radiation-induced generation-recombination currents in bipolar devices.« less

Electrical characterisation of defects in wide bandgap semiconductors

NASA Astrophysics Data System (ADS)

Elsherif, Osama S.

Defects usually have a very large influence on the semiconductor material properties and hence on fabricated electronic devices. The nature and properties of defects in semiconducting materials can be investigated by applying electrical characterization techniques such as thermal admittance spectroscopy (TAS), deep level transient spectroscopy (DLTS) and high resolution Laplace-DLTS measurements. This dissertation presents the electrical characterisation of two different wide bandgap semiconducting materials (polycrystalline diamond and GaN) which have both recently attracted a great deal of attention because of their potential applications in the fields of power electronics and optoelectronics. Raman spectroscopy, I-V and C-V measurements were carried out as supporting experiments for the above investigations. The first part of this work focuses on studying the effect of B concentration on the electronic states in polycrystalline diamond thin films grown on silicon by the hot filament chemical vapour deposition method. A combination of high-resolution LDLTS and direct-capture cross-section measurements was used to investigate whether the deep electronic states present in the layers originated from point or extended defects. There was good agreement between data on deep electronic levels obtained from DLTS and TAS experiments. A number of hole traps have been detected; the majority of these levels show an unusual dependence of the DLTS signal on the fill pulse duration which is interpreted as possibly the levels are part of extended defects within the grain boundaries. In contrast, a defect level found in a more highly doped film, with an activation energy of -0.37 eV, exhibited behaviour characteristic of an isolated point defect, which we attribute to B-related centres in the bulk diamond, away from the dislocations. The second part of this thesis presents electrical measurements carried out at temperatures up to 450 K in order to study the electronic states associated with Mg in Mg-doped GaN films grown on sapphire by metalorganic vapour phase epitaxy, and to determine how these are affected by the threading dislocation density (TDD). Two different buffer layer schemes between the film and the sapphire substrate were used, giving rise to different TDDs in the GaN. Admittance spectroscopy of the films finds a single impurity-related acceptor level. It is observed in theses experiments that admittance spectroscopy detects no traps that can be attributed to extended defects, despite the fact that the dislocations are well-known to be active recombination centres. This unexpected finding is discussed in detail.

Electrical characterisation of defects in wide bandgap semiconductors

NASA Astrophysics Data System (ADS)

Elsherif, Osama S.

Defects usually have a very large influence on the semiconductor material properties and hence on fabricated electronic devices. The nature and properties of defects in semiconducting materials can be investigated by applying electrical characterization techniques such as thermal admittance spectroscopy (TAS), deep level transient spectroscopy (DLTS) and high resolution Laplace-DLTS measurements. This dissertation presents the electrical characterisation of two different wide bandgap semiconducting materials (polycrystalline diamond and GaN) which have both recently attracted a great deal of attention because of their potential applications in the fields of power electronics and optoelectronics. Raman spectroscopy, I-V and C-V measurements were carried out as supporting experiments for the above investigations.The first part of this work focuses on studying the effect of B concentration on the electronic states in polycrystalline diamond thin films grown on silicon by the hot filament chemical vapour deposition method. A combination of high-resolution LDLTS and direct-capture cross-section measurements was used to investigate whether the deep electronic states present in the layers originated from point or extended defects. There was good agreement between data on deep electronic levels obtained from DLTS and TAS experiments. A number of hole traps have been detected; the majority of these levels show an unusual dependence of the DLTS signal on the fill pulse duration which is interpreted as possibly the levels are part of extended defects within the grain boundaries. In contrast, a defect level found in a more highly doped film, with an activation energy of -0.37 eV, exhibited behaviour characteristic of an isolated point defect, which we attribute to B-related centres in the bulk diamond, away from the dislocations.The second part of this thesis presents electrical measurements carried out at temperatures up to 450 K in order to study the electronic states associated with Mg in Mg-doped GaN films grown on sapphire by metalorganic vapour phase epitaxy, and to determine how these are affected by the threading dislocation density (TDD). Two different buffer layer schemes between the film and the sapphire substrate were used, giving rise to different TDDs in the GaN. Admittance spectroscopy of the films finds a single impurity-related acceptor level. It is observed in theses experiments that admittance spectroscopy detects no traps that can be attributed to extended defects, despite the fact that the dislocations are well-known to be active recombination centres. This unexpected finding is discussed in detail.

The Challenge to Situate Digital Learning Technologies in Preservice Teacher Mathematics Education

ERIC Educational Resources Information Center

McDonald, Susan

2012-01-01

This paper focuses on how preservice primary teachers can be supported to embrace digital learning technologies (DLTs) in their teaching of mathematics. The nature of the instruction and the assessment in the final mathematics unit of the bachelor of education program were changed. Despite being tagged as "tech-savvy," preservice…

Temperature-Dependent Photoluminescence Imaging and Characterization of a Multi-Crystalline Silicon Solar Cell Defect Area

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, S.; Yan, F.; Li, J.

2011-01-01

Photoluminescence (PL) imaging is used to detect areas in multi-crystalline silicon that appear dark in band-to-band imaging due to high recombination. Steady-state PL intensity can be correlated to effective minority-carrier lifetime, and its temperature dependence can provide additional lifetime-limiting defect information. An area of high defect density has been laser cut from a multi-crystalline silicon solar cell. Both band-to-band and defect-band PL imaging have been collected as a function of temperature from {approx}85 to 350 K. Band-to-band luminescence is collected by an InGaAs camera using a 1200-nm short-pass filter, while defect band luminescence is collected using a 1350-nm long passmore » filter. The defect band luminescence is characterized by cathodoluminescence. Small pieces from adjacent areas within the same wafer are measured by deep-level transient spectroscopy (DLTS). DLTS detects a minority-carrier electron trap level with an activation energy of 0.45 eV on the sample that contained defects as seen by imaging.« less

Temperature-Dependent Photoluminescence Imaging and Characterization of a Multi-Crystalline Silicon Solar Cell Defect Area: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, S.; Yan, F.; Li, J.

2011-07-01

Photoluminescence (PL) imaging is used to detect areas in multi-crystalline silicon that appear dark in band-to-band imaging due to high recombination. Steady-state PL intensity can be correlated to effective minority-carrier lifetime, and its temperature dependence can provide additional lifetime-limiting defect information. An area of high defect density has been laser cut from a multi-crystalline silicon solar cell. Both band-to-band and defect-band PL imaging have been collected as a function of temperature from ~85 to 350 K. Band-to-band luminescence is collected by an InGaAs camera using a 1200-nm short-pass filter, while defect band luminescence is collected using a 1350-nm long passmore » filter. The defect band luminescence is characterized by cathodo-luminescence. Small pieces from adjacent areas within the same wafer are measured by deep-level transient spectroscopy (DLTS). DLTS detects a minority-carrier electron trap level with an activation energy of 0.45 eV on the sample that contained defects as seen by imaging.« less

A novel one-step real-time multiplex PCR assay to detect Streptococcus agalactiae presence and serotypes Ia, Ib, and III.

PubMed

Furfaro, Lucy L; Chang, Barbara J; Payne, Matthew S

2017-09-01

Streptococcus agalactiae is the leading cause of early-onset neonatal sepsis. Culture-based screening methods lack the sensitivity of molecular assays and do not indicate serotype; a potentially important virulence marker. We aimed to develop a multiplex PCR to detect S. agalactiae while simultaneously identifying serotypes Ia, Ib, and III; commonly associated with infant disease. Primers were designed to target S. agalactiae serotype-specific cps genes and the dltS gene. The assay was validated with 512 vaginal specimens from pregnant women. 112 (21.9%) were dltS positive, with 14.3%, 0.9%, and 6.3% of these identified as cps Ia, Ib, and III, respectively. Our assay is a specific and sensitive method to simultaneously detect S. agalactiae and serotypes Ia, Ib, and III in a single step. It is of high significance for clinical diagnostic applications and also provides epidemiological data on serotype, information that may be important for vaccine development and other targeted non-antibiotic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Exceptional gettering response of epitaxially grown kerfless silicon

DOE PAGES

Powell, D. M.; Markevich, V. P.; Hofstetter, J.; ...

2016-02-08

The bulk minority-carrier lifetime in p- and n-type kerfless epitaxial (epi) crystalline silicon wafers is shown to increase >500 during phosphorus gettering. We employ kinetic defect simulations and microstructural characterization techniques to elucidate the root cause of this exceptional gettering response. Simulations and deep-level transient spectroscopy (DLTS) indicate that a high concentra- tion of point defects (likely Pt) is “locked in” during fast (60 C/min) cooling during epi wafer growth. The fine dispersion of moderately fast-diffusing recombination-active point defects limits as-grown lifetime but can also be removed during gettering, confirmed by DLTS measurements. Synchrotron-based X-ray fluorescence microscopy indicates metal agglomeratesmore » at structural defects, yet the structural defect density is sufficiently low to enable high lifetimes. Consequently, after phosphorus diffusion gettering, epi silicon exhibits a higher lifetime than materials with similar bulk impurity contents but higher densities of structural defects, including multicrystalline ingot and ribbon silicon materials. As a result, device simulations suggest a solar-cell efficiency potential of this material >23%.« less

The effects of lithium counterdoping on radiation damage and annealing in n(+)p silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Brandhorst, H. W., Jr.; Mehta, S.; Swartz, C. K.

1984-01-01

Boron-doped silicon n(+)p solar cells were counterdoped with lithium by ion implantation and the resultant n(+)p cells irradiated by 1 MeV electrons. Performance parameters were determined as a function of fluence and a deep level transient spectroscopy (DLTS) study was conducted. The lithium counterdoped cells exhibited significantly increased radiation resistance when compared to boron doped control cells. Isochronal annealing studies of cell performance indicate that significant annealing occurs at 100 C. Isochronal annealing of the deep level defects showed a correlation between a single defect at E sub v + 0.43 eV and the annealing behavior of short circuit current in the counterdoped cells. The annealing behavior was controlled by dissociation and recombination of this defect. The DLTS studies showed that counterdoping with lithium eliminated three deep level defects and resulted in three new defects. The increased radiation resistance of the counterdoped cells is due to the interaction of lithium with oxygen, single vacancies and divacancies. The lithium-oxygen interaction is the most effective in contributing to the increased radiation resistance.

Processing-Induced Electrically Active Defects in Black Silicon Nanowire Devices.

PubMed

Carapezzi, Stefania; Castaldini, Antonio; Mancarella, Fulvio; Poggi, Antonella; Cavallini, Anna

2016-04-27

Silicon nanowires (Si NWs) are widely investigated nowadays for implementation in advanced energy conversion and storage devices, as well as many other possible applications. Black silicon (BSi)-NWs are dry etched NWs that merge the advantages related to low-dimensionality with the special industrial appeal connected to deep reactive ion etching (RIE). In fact, RIE is a well established technique in microelectronics manufacturing. However, RIE processing could affect the electrical properties of BSi-NWs by introducing deep states into their forbidden gap. This work applies deep level transient spectroscopy (DLTS) to identify electrically active deep levels and the associated defects in dry etched Si NW arrays. Besides, the successful fitting of DLTS spectra of BSi-NWs-based Schottky barrier diodes is an experimental confirmation that the same theoretical framework of dynamic electronic behavior of deep levels applies in bulk as well as in low dimensional structures like NWs, when quantum confinement conditions do not occur. This has been validated for deep levels associated with simple pointlike defects as well as for deep levels associated with defects with richer structures, whose dynamic electronic behavior implies a more complex picture.

DLTS analysis of amphoteric interface defects in high-TiO{sub 2} MOS structures prepared by sol-gel spin-coating

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Arvind; Mondal, Sandip; Rao, K. S. R. Koteswara, E-mail: ksrkrao@physics.iisc.ernet.in, E-mail: raoksrk@gmail.com

2015-11-15

High-κ TiO{sub 2} thin films have been fabricated from a facile, combined sol – gel spin – coating technique on p and n type silicon substrate. XRD and Raman studies headed the existence of anatase phase of TiO{sub 2} with a small grain size of 18 nm. The refractive index ‘n’ quantified from ellipsometry is 2.41. AFM studies suggest a high quality, pore free films with a fairly small surface roughness of 6 Å. The presence of Ti in its tetravalent state is confirmed by XPS analysis. The defect parameters observed at the interface of Si/TiO{sub 2} were studied bymore » capacitance – voltage (C – V) and deep level transient spectroscopy (DLTS). The flat – band voltage (V{sub FB}) and the density of slow interface states estimated are – 0.9, – 0.44 V and 5.24×10{sup 10}, 1.03×10{sup 11} cm{sup −2}; for the NMOS and PMOS capacitors, respectively. The activation energies, interface state densities and capture cross – sections measured by DLTS are E{sub V} + 0.30, E{sub C} – 0.21 eV; 8.73×10{sup 11}, 6.41×10{sup 11} eV{sup −1} cm{sup −2} and 5.8×10{sup −23}, 8.11×10{sup −23} cm{sup 2} for the NMOS and PMOS structures, respectively. A low value of interface state density in both P- and N-MOS structures makes it a suitable alternate dielectric layer for CMOS applications. And also very low value of capture cross section for both the carriers due to the amphoteric nature of defect indicates that the traps are not aggressive recombination centers and possibly can not contribute to the device operation to a large extent.« less

A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314).

PubMed

Schafer, Eric S; Rau, Rachel E; Berg, Stacey; Liu, Xiaowei; Minard, Charles G; D'Adamo, David; Scott, Rachael; Reyderman, Larisa; Martinez, Gresel; Devarajan, Sandhya; Reid, Joel M; Fox, Elizabeth; Weigel, Brenda J; Blaney, Susan M

2018-05-02

Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m 2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m 2 /dose on days 1 and 8 of a 21-day cycle. © 2018 Wiley Periodicals, Inc.

Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garces, Yolanda I.; Okuno, Scott H.; Schild, Steven E.

Purpose: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). Methods and Materials: Treatment began with two cycles of topotecan (1 mg/m{sup 2}) Days 1 to 5 and paclitaxel (175 mg/m{sup 2}) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard 'cohortsmore » of 3' design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m{sup 2}) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade {>=}4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade {>=}3 dyspnea, or Grade {>=}2 pneumonitis. Results: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade {>=}3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. Conclusion: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine.« less

Superlattices and Semiconductor/Semiconductor Interfaces.

DTIC Science & Technology

1984-01-17

the electron effective ’J. N. Schulman and T. C. Mc"il AppI. Phys. Lett 34. 66311979). masse in the snuff band-gap alloys, suggesting reducedp- 3.P...et al. " have made DLTS measurements on n-type, , lead to the loss of electrically active indium through the for- indium doped CdTe films grown on BaF

HgCdTe Surface and Defect Study Program.

DTIC Science & Technology

1984-07-01

double layer heterojunction (DLHJ) devices. There are however many complications on this once we consider implanted junctions, LWIR devices or even the...It is not possible from this measurement to discriminate between real interface states and charge nonuniformities . Admittance spectroscopy (discussed...earlier) and deep level transient spectroscopy (DLTS) are not usually affected by these nonuniformities due to their observation of a speci- fic

Joint Services Electronics Program.

DTIC Science & Technology

1987-12-31

and annealing, using deep level transient spectroscopy (DLTS), and the effects of co-implantation on 4l the activation of amphoteric dopants and...theriithe study of optical quantum effects with emphasis on nonlinear optical phenomena. For example, a significant accomplishment write-up describes...Millimeter-Wave Array Components Tatsuo Itoh A number of novel solid state devices such as metal semiconductor field effect transistors (MESFET

Characterization of iron in silicon by low-temperature photoluminescence and deep-level transient spectroscopy

NASA Astrophysics Data System (ADS)

Nakamura, Minoru; Murakami, Susumu; Udono, Haruhiko

2018-03-01

We investigate the relationship between the intensity of band-edge (BDE) photoluminescence (PL) from 10 to 70 K and the concentration of iron diffused in boron-doped p-type silicon. Because of the nonradiative recombination activity of the interstitial iron-boron complex (FeiB center), the BDE-PL intensity at each temperature varies distinctively and systematically with the iron concentration, which means that this method has the potential to make the accurate measurements of a wide range of interstitial iron concentrations in silicon. The iron precipitates formed in the bulk and/or at the surface are found to exert much weaker recombination activity for excess carriers than FeiB center by exploiting both PL and deep-level transient spectroscopy (DLTS) measurements. The unexpected enhancement in BDE-PL intensity from iron-diffused silicon between 20 and 50 K is attributed to the passivation of the Si-oxide/Si interface by iron. For the samples diffused with trace amounts of iron, the iron concentration within 20 μm of the surface is significantly greater than that in the bulk, as measured by DLTS. This result is tentatively attributed to the affinity of iron with the Si-oxide.

Defect levels of semi-insulating CdMnTe:In crystals

NASA Astrophysics Data System (ADS)

Kim, K. H.; Bolotinikov, A. E.; Camarda, G. S.; Hossain, A.; Gul, R.; Yang, G.; Cui, Y.; Prochazka, J.; Franc, J.; Hong, J.; James, R. B.

2011-06-01

Using photoluminescence (PL) and current deep-level transient spectroscopy (I-DLTS), we investigated the electronic defects of indium-doped detector-grade CdMnTe:In (CMT:In) crystals grown by the vertical Bridgman method. We similarly analyzed CdZnTe:In (CZT:In) and undoped CdMnTe (CMT) crystals grown under the amount of same level of excess Te and/or indium doping level to detail the fundamental properties of the electronic defect structure more readily. Extended defects, existing in all the samples, were revealed by synchrotron white beam x-ray diffraction topography and scanning electron microscopy. The electronic structure of CMT is very similar to that of CZT, with shallow traps, A-centers, Cd vacancies, deep levels, and Te antisites. The 1.1-eV deep level, revealed by PL in earlier studies of CZT and CdTe, were attributed to dislocation-induced defects. In our I-DLTS measurements, the 1.1-eV traps showed different activation energies with applied bias voltage and an exponential dependence on the trap-filling time, which are typical characteristics of dislocation-induced defects. We propose a new defect-trap model for indium-doped CMT crystals.

A Phase I Study of UFT/Leucovorin, Carboplatin, and Paclitaxel in Combination With External Beam Radiation Therapy for Advanced Esophageal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Czito, Brian G.; Cohen, Darrel P.; Kelsey, Chris R.

Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination ofmore » dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates. Results: Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response. Conclusions: Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.« less

Electrical characterization and comparison of CIGS solar cells made with different structures and fabrication techniques

DOE PAGES

Garris, Rebekah L.; Johnston, Steven; Li, Jian V.; ...

2017-08-31

In a previous study, we reported on Cu(In,Ga)Se2-based (CIGS) solar cell samples collected from different research laboratories and industrial companies with the purpose of understanding the range of CIGS materials that can lead to high-quality and high-efficiency solar panels. Here, we report on electrical measurements of those same samples. Electron-beam induced current and time-resolved photoluminescence (TRPL) gave insights about the collection probability and the lifetime of carriers generated in each absorber. Capacitance and drive-level capacitance profiling revealed nonuniformity in carrier-density profiles. Admittance spectroscopy revealed small activation energies (= 0.03 eV) indicative of the inversion strength, larger activation energies (> 0.1more » eV) reflective of thermal activation of absorber conductivity and a deeper defect level. Deep-level transient spectroscopy (DLTS) probed deep hole-trapping defects and showed that all samples in this study had a majority-carrier defect with activation energy between 0.3 eV and 0.9 eV. Optical-DLTS revealed deep electron-trapping defects in several of the CIGS samples. This work focused on revealing similarities and differences between high-quality CIGS solar cells made with various structures and fabrication techniques.« less

Electrical characterization and comparison of CIGS solar cells made with different structures and fabrication techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garris, Rebekah L.; Johnston, Steven; Li, Jian V.

In a previous study, we reported on Cu(In,Ga)Se2-based (CIGS) solar cell samples collected from different research laboratories and industrial companies with the purpose of understanding the range of CIGS materials that can lead to high-quality and high-efficiency solar panels. Here, we report on electrical measurements of those same samples. Electron-beam induced current and time-resolved photoluminescence (TRPL) gave insights about the collection probability and the lifetime of carriers generated in each absorber. Capacitance and drive-level capacitance profiling revealed nonuniformity in carrier-density profiles. Admittance spectroscopy revealed small activation energies (= 0.03 eV) indicative of the inversion strength, larger activation energies (> 0.1more » eV) reflective of thermal activation of absorber conductivity and a deeper defect level. Deep-level transient spectroscopy (DLTS) probed deep hole-trapping defects and showed that all samples in this study had a majority-carrier defect with activation energy between 0.3 eV and 0.9 eV. Optical-DLTS revealed deep electron-trapping defects in several of the CIGS samples. This work focused on revealing similarities and differences between high-quality CIGS solar cells made with various structures and fabrication techniques.« less

Band-Like Behavior of Localized States of Metal Silicide Precipitate in Silicon

NASA Astrophysics Data System (ADS)

Bondarenko, Anton; Vyvenko, Oleg

2018-03-01

Deep-level transient spectroscopy (DLTS) investigations of energy levels of charge-carrier traps associated with precipitates of metal silicide often show that they behave not like localized monoenergetic traps but as a continuous density of allowed states in the bandgap with fast carrier exchange between these states, so-called band-like behavior. This kind of behavior was ascribed to the dislocation loop bounding the platelet, which in addition exhibits an attractive potential caused by long-range elastic strain. In previous works, the presence of the dislocation-related deformation potential in combination with the external electric field of the Schottky diode was included to obtain a reasonable fit of the proposed model to experimental data. Another well-known particular property of extended defects—the presence of their own strong electric field in their vicinity that is manifested in the logarithmic kinetics of electron capture—was not taken into account. We derive herein a theoretical model that takes into account both the external electric field and the intrinsic electric field of dislocation self-charge as well as its deformation potential, which leads to strong temporal variation of the activation energy during charge-carrier emission. We performed numerical simulations of the DLTS spectra based on such a model for a monoenergetic trap, finding excellent agreement with available experimental data.

Radiation degradation prediction for InGaP solar cells by using appropriate estimation method for displacement threshold energy

NASA Astrophysics Data System (ADS)

Okuno, Y.; Okuda, S.; Akiyoshi, M.; Oka, T.; Harumoto, M.; Omura, K.; Kawakita, S.; Imaizumi, M.; Messenger, S. R.; Lee, K. H.; Yamaguchi, M.

2017-09-01

InGaP solar cells are not predicted to be susceptible to displacement damage by irradiation with electrons at energies lower than 100 keV from non-ionizing energy loss (NIEL) calculations. However, it is recently observed that InGaP solar cells are shown to degrade by irradiation with 60 keV electrons. This degradation is considered to be caused by radiation defects but is not clear. In this study, the kind of the defects generated by electrons at energies lower than 100 keV is found by deep-level transient spectroscopy (DLTS). The result of DLTS indicates that the prediction of primary knock-on atoms by using the radiation damage model is different from the experiment. In order to suggest the generation mechanism of radiation defects, we propose a new displacement threshold energy (Ed) by using a new technique in which NIEL and the introduction rate of radiation defects are combined. The degradation prediction by using estimated Ed is found to agree well with the degradation of electric power of InGaP solar cells irradiated by low-energy electrons. From the theory of radiation defects, we propose a new obtaining process of suitable degradation prediction by the displacement damage dose method.

Deep level defects in dilute GaAsBi alloys grown under intense UV illumination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mooney, P. M.; Tarun, Marianne; Beaton, D. A.

2016-07-21

Dilute GaAs1-xBix alloys exhibiting narrow band edge photoluminescence (PL) were recently grown by molecular beam epitaxy (MBE) with the growth surface illuminated by intense UV radiation. To investigate whether the improved optical quality of these films results from a reduction in the concentration of deep level defects, p+/n and n+/p junction diodes were fabricated on both the illuminated and dark areas of several samples. Deep Level Transient Spectroscopy (DLTS) measurements show that the illuminated and dark areas of both the n- and p-type GaAs1-xBix epi-layers have similar concentrations of near mid-gap electron and hole traps, in the 1015 cm-3 range.more » Thus the improved PL spectra cannot be explained by a reduction in non-radiative recombination at deep level defects. We note that carrier freeze-out above 35 K is significantly reduced in the illuminated areas of the p-type GaAs1-xBix layers compared to the dark areas, allowing the first DLTS measurements of defect energy levels close to the valence band edge. These defect levels may account for differences in the PL spectra from the illuminated and dark areas of un-doped layers with a similar Bi fraction.« less

Collaborative Research and Development (CR&D). Task Order 0036: Physical and Chemical Processes of Operating Electronic Devices

DTIC Science & Technology

2006-09-01

actually seen. A. Hierro , … S. A. Ringel et al., Phys. Stat. Sol (b) 228, 937 (2001). Ohio State U. Use DLTS and DLOS (Deep Level Optical Spectroscopy...to threading dislocations. Also see A. Hierro et al., APL 76, 3064 (2000), where traps at EC-ET=0.58-0.62, 1.35, 2.57-2.64, 3.22eV are seen in GaN

Electronic properties of defects in silicon and related materials

NASA Astrophysics Data System (ADS)

Mitromara, Niki

Efforts in the current semiconductor industry are focused on the production of smaller, more efficient and inexpensive devices of higher packing density. As silicon is the dominant semiconductor implemented for the fabrication of the majority of semiconductor devices, perpetual research has focused on the improvement of its properties and the realisation of the most efficient structures. This thesis presents the electrical characterisation of two different diode structures that are important for the present and future generations of electronic devices.The first part of the thesis is focused on the electrical characterisation of Ultra-Shallow Junction (USJs) Si diodes. Both p+n and n+p USJ structures that contained different implants were examined. These were very highly doped and intended to simulate the situation where a doping well is formed after heavy doping in Si for the fabrication of transistors currently used in Complementary-Metal-Oxide-Semiconductor (CMOS) technology. The implanted USJ diodes were provided by NXP, Belgium and contact deposition was performed before their electrical characterisation as part of this project. Subsequently the p+n and n+p USJ diodes were characterised by the use of Capacitance-Voltage (CV), Current-Voltage (IV), Deep Level Transient Spectroscopy (DLTS) and high resolution Laplace DLTS (LDLTS). DLTS and LDLTS are very powerful spectroscopic techniques for the profiling of defects in the bandgap of a semiconductor as well as for the identification of the electrical signatures of these defects. Transient-Enhanced Diffusion (TED) related defects were detected in these diodes as the presence of mainly carbon-related interstitial complexes was observed. In addition, certain vacancy or vacancy-dopant related levels were also discerned.The second part of this thesis presents the electrical characterisation from Schottky p-diamond/p-Si and p-diamond/n-Si p-n diodes. These diodes were readily provided, grown by the Chemical Vapour Deposition (CVD) technique, for the electrical characterisation that was performed as part of this project. The purpose of characterising both Schottky and p-n diamond on Si diodes was to detect defects near the surface of the films and near the interface with Si and hence provide a comparison between defects present at the beginning and end of growth. More defects were found near the interface with Si and the majority of observed defects were related to extended defects while the presence of grain boundaries in polycrystalline diamond was discussed.

High-energy electron-induced damage production at room temperature in aluminum-doped silicon

NASA Technical Reports Server (NTRS)

Corbett, J. W.; Cheng, L. J.; Jaworowski, A.; Karins, J. P.; Lee, Y. H.; Lindstroem, L.; Mooney, P. M.; Oehrlen, G.; Wang, K. L.

1979-01-01

DLTS and EPR measurements are reported on aluminum-doped silicon that was irradiated at room temperature with high-energy electrons. Comparisons are made to comparable experiments on boron-doped silicon. Many of the same defects observed in boron-doped silicon are also observed in aluminum-doped silicon, but several others were not observed, including the aluminum interstitial and aluminum-associated defects. Damage production modeling, including the dependence on aluminum concentration, is presented.

Quality-of-Life (QOL) during Screening for Phase 1 Trial Studies in Patients with Advanced Solid Tumors and Its Impact on Risk for Serious Adverse Events.

PubMed

Anwar, Sidra; Tan, Wei; Hong, Chi-Chen; Admane, Sonal; Dozier, Askia; Siedlecki, Francine; Whitworth, Amy; DiRaddo, Ann Marie; DePaolo, Dawn; Jacob, Sandra M; Ma, Wen Wee; Miller, Austin; Adjei, Alex A; Dy, Grace K

2017-06-26

Background : Serious adverse events (SAEs) and subject replacements occur frequently in phase 1 oncology clinical trials. Whether baseline quality-of-life (QOL) or social support can predict risk for SAEs or subject replacement among these patients is not known. Methods : Between 2011-2013, 92 patients undergoing screening for enrollment into one of 22 phase 1 solid tumor clinical trials at Roswell Park Cancer Institute were included in this study. QOL Questionnaires (EORTC QLQ-C30 and FACT-G), Medical Outcomes Study Social Support Survey (MOSSSS), Charlson comorbidity scores (CCS) and Royal Marsden scores (RMS) were obtained at baseline. Frequency of dose limiting toxicities (DLTs), subject replacement and SAEs that occurred within the first 4 cycles of treatment were recorded. Fisher's exact test and Mann-Whitney-Wilcoxon test were used to study the association between categorical and continuous variables, respectively. A linear transformation was used to standardize QOL scores. p -value ≤ 0.05 was considered statistically significant. Results : Baseline QOL, MOSSSS, CCS and RMS were not associated with subject replacement nor DLTs. Baseline EORTC QLQ-C30 scores were significantly lower among patients who encountered SAEs within the first 4 cycles ( p = 0.04). Conclusions : Lower (worse) EORTC QLQ-C30 score at baseline is associated with SAE occurrence during phase 1 oncology trials.

Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity.

PubMed

Awada, Ahmad; Dumez, Herlinde; Aftimos, Philippe G; Costermans, Jo; Bartholomeus, Sylvie; Forceville, Kathleen; Berghmans, Thierry; Meeus, Marie-Anne; Cescutti, Jessica; Munzert, Gerd; Pilz, Korinna; Liu, Dan; Schöffski, Patrick

2015-06-01

This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

Electrical characterisation of deep level defects in Be-doped AlGaAs grown on (100) and (311)A GaAs substrates by MBE

PubMed Central

2011-01-01

The growth of high mobility two-dimensional hole gases (2DHGs) using GaAs-GaAlAs heterostructures has been the subject of many investigations. However, despite many efforts hole mobilities in Be-doped structures grown on (100) GaAs substrate remained considerably lower than those obtained by growing on (311)A oriented surface using silicon as p-type dopant. In this study we will report on the properties of hole traps in a set of p-type Be-doped Al0.29Ga0.71As samples grown by molecular beam epitaxy on (100) and (311)A GaAs substrates using deep level transient spectroscopy (DLTS) technique. In addition, the effect of the level of Be-doping concentration on the hole deep traps is investigated. It was observed that with increasing the Be-doping concentration from 1 × 1016 to 1 × 1017 cm-3 the number of detected electrically active defects decreases for samples grown on (311)A substrate, whereas, it increases for (100) orientated samples. The DLTS measurements also reveal that the activation energies of traps detected in (311)A are lower than those in (100). From these findings it is expected that mobilities of 2DHGs in Be-doped GaAs-GaAlAs devices grown on (311)A should be higher than those on (100). PMID:21711687

Advanced Techniques for Transmutation Compensation of Extrinsic Silicon Detectors.

DTIC Science & Technology

1980-10-01

generally better than 1..2 R . EPR Spectrometer NMicroscopic defect structure is determined by elec- tron paramagnetic resonance (HIlP ) or, as it is more...cnm- monly known, elet ron spin resonance ( I;R . The 1,S R instrument used for th(,se experimnents is -I COllVttiOl1l1 X-band (9 (;ll:) SpectroletoPr...226 75. DLTS electron traps in n-type neutron irra- diated Si as a function of isohronal anneals (100 Hz, th = 1.8 x 1015 n

Identification and Carrier Dynamics of the Dominant Lifetime Limiting Defect in n(-) 4H-SiC Epitaxial Layers

DTIC Science & Technology

2009-01-01

defects, measured by DLTS, and vacancies, detected by positron annihilation studies, as a function of thermal annealing temperature. The similarity in... applications and materials science a st a tu s so li d i www.pss-a.comp h y si ca Feature Article Identification and carrier dynamics of the dominant...stability and chemical inertness – make them ideal for applications that demand high power and/or high fre- quency operation that is well beyond the

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

PubMed

Tahara, M; Araki, K; Okano, S; Kiyota, N; Fuse, N; Minashi, K; Yoshino, T; Doi, T; Zenda, S; Kawashima, M; Ogino, T; Hayashi, R; Minami, H; Ohtsu, A

2011-01-01

we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

Hole traps associated with high-concentration residual carriers in p-type GaAsN grown by chemical beam epitaxy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elleuch, Omar, E-mail: mr.omar.elleuch@gmail.com; Wang, Li; Lee, Kan-Hua

2015-01-28

The hole traps associated with high background doping in p-type GaAsN grown by chemical beam epitaxy are studied based on the changes of carrier concentration, junction capacitance, and hole traps properties due to the annealing. The carrier concentration was increased dramatically with annealing time, based on capacitance–voltage (C–V) measurement. In addition, the temperature dependence of the junction capacitance (C–T) was increased rapidly two times. Such behavior is explained by the thermal ionization of two acceptor states. These acceptors are the main cause of high background doping in the film, since the estimated carrier concentration from C–T results explains the measuredmore » carrier concentration at room temperature using C–V method. The acceptor states became shallower after annealing, and hence their structures are thermally unstable. Deep level transient spectroscopy (DLTS) showed that the HC2 hole trap was composed of two signals, labeled HC21 and HC22. These defects correspond to the acceptor levels, as their energy levels obtained from DLTS are similar to those deduced from C–T. The capture cross sections of HC21 and HC22 are larger than those of single acceptors. In addition, their energy levels and capture cross sections change in the same way due to the annealing. This tendency suggests that HC21 and HC22 signals originate from the same defect which acts as a double acceptor.« less

A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer.

PubMed

Michael, M; Zalcberg, J; Gibbs, P; Lipton, L; Gouillou, M; Jefford, M; McArthur, G; Copeman, M; Lynch, K; Tebbutt, N C

2013-02-01

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.

Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors.

PubMed

Molife, L Rhoda; Yan, Li; Vitfell-Rasmussen, Joanna; Zernhelt, Adriane M; Sullivan, Daniel M; Cassier, Philippe A; Chen, Eric; Biondo, Andrea; Tetteh, Ernestina; Siu, Lillian L; Patnaik, Amita; Papadopoulos, Kyriakos P; de Bono, Johann S; Tolcher, Anthony W; Minton, Susan

2014-01-03

Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.

Hydrogen passivation of titanium impurities in silicon: Effect of doping conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Santos, P.; Coutinho, J., E-mail: jose.coutinho@ua.pt; Torres, V. J. B.

2014-07-21

While the contamination of solar silicon by fast diffusing transition metals can be now limited through gettering, much attention has been drawn to the slow diffusing species, especially the early 3d and 4d elements. To some extent, hydrogen passivation has been successful in healing many deep centers, including transition metals in Si. Recent deep-level transient spectroscopy (DLTS) measurements concerning hydrogen passivation of Ti revealed the existence of at least four electrical levels related to Ti{sub i}H{sub n} in the upper-half of the gap. These findings challenge the existing models regarding both the current level assignment as well as the structure/speciesmore » involved in the defects. We revisit this problem by means of density functional calculations and find that progressive hydrogenation of interstitial Ti is thermodynamically stable in intrinsic and n-doped Si. Full passivation may not be possible to attain in p-type Si as Ti{sub i}H{sub 3} and Ti{sub i}H{sub 4} are metastable against dissociation and release of bond-centered protons. All DLTS electron traps are assigned, namely, E40′ to Ti{sub i}H(-/0), E170′ to Ti{sub i}H{sub 3}(0/+), E(270) to Ti{sub i}H{sub 2}(0/+), and E170 to Ti{sub i}H(0/+) transitions. Ti{sub i}H{sub 4} is confirmed to be electrically inert.« less

Donor and double-donor transitions of the carbon vacancy related EH{sub 6∕7} deep level in 4H-SiC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Booker, I. D., E-mail: ianbo@ifm.liu.se; Janzén, E., E-mail: erija@ifm.liu.se; Son, N. T.

Using medium- and high-resolution multi-spectra fitting of deep level transient spectroscopy (DLTS), minority carrier transient spectroscopy (MCTS), optical O-DLTS and optical-electrical (OE)-MCTS measurements, we show that the EH{sub 6∕7} deep level in 4H-SiC is composed of two strongly overlapping, two electron emission processes with thermal activation energies of 1.49 eV and 1.58 eV for EH{sub 6} and 1.48 eV and 1.66 eV for EH{sub 7}. The electron emission peaks of EH{sub 7} completely overlap while the emission peaks of EH{sub 6} occur offset at slightly different temperatures in the spectra. OE-MCTS measurements of the hole capture cross section σ{sub p0}(T) in p-type samples revealmore » a trap-Auger process, whereby hole capture into the defect occupied by two electrons leads to a recombination event and the ejection of the second electron into the conduction band. Values of the hole and electron capture cross sections σ{sub n}(T) and σ{sub p}(T) differ strongly due to the donor like nature of the deep levels and while all σ{sub n}(T) have a negative temperature dependence, the σ{sub p}(T) appear to be temperature independent. Average values at the DLTS measurement temperature (∼600 K) are σ{sub n2+}(T) ≈ 1 × 10{sup −14} cm{sup 2}, σ{sub n+}(T) ≈ 1 × 10{sup −14} cm{sup 2}, and σ{sub p0}(T) ≈ 9 × 10{sup −18} cm{sup 2} for EH{sub 6} and σ{sub n2+}(T) ≈ 2 × 10{sup −14} cm{sup 2}, σ{sub n+}(T) ≈ 2 × 10{sup −14} cm{sup 2}, σ{sub p0}(T) ≈ 1 × 10{sup −20} cm{sup 2} for EH{sub 7}. Since EH{sub 7} has already been identified as a donor transition of the carbon vacancy, we propose that the EH{sub 6∕7} center in total represents the overlapping first and second donor transitions of the carbon vacancy defects on both inequivalent lattice sites.« less

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

PubMed

Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R

2014-04-01

Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

A physical model for the reverse leakage current in (In,Ga)N/GaN light-emitting diodes based on nanowires

DOE Office of Scientific and Technical Information (OSTI.GOV)

Musolino, M.; Treeck, D. van, E-mail: treeck@pdi-berlin.de; Tahraoui, A.

2016-01-28

We investigated the origin of the high reverse leakage current in light emitting diodes (LEDs) based on (In,Ga)N/GaN nanowire (NW) ensembles grown by molecular beam epitaxy on Si substrates. To this end, capacitance deep level transient spectroscopy (DLTS) and temperature-dependent current-voltage (I-V) measurements were performed on a fully processed NW-LED. The DLTS measurements reveal the presence of two distinct electron traps with high concentrations in the depletion region of the p-i-n junction. These band gap states are located at energies of 570 ± 20 and 840 ± 30 meV below the conduction band minimum. The physical origin of these deep level states is discussed. Themore » temperature-dependent I-V characteristics, acquired between 83 and 403 K, show that different conduction mechanisms cause the observed leakage current. On the basis of all these results, we developed a quantitative physical model for charge transport in the reverse bias regime. By taking into account the mutual interaction of variable range hopping and electron emission from Coulombic trap states, with the latter being described by phonon-assisted tunnelling and the Poole-Frenkel effect, we can model the experimental I-V curves in the entire range of temperatures with a consistent set of parameters. Our model should be applicable to planar GaN-based LEDs as well. Furthermore, possible approaches to decrease the leakage current in NW-LEDs are proposed.« less

Safety and pharmacokinetics of veliparib extended-release in patients with advanced solid tumors: a phase I study.

PubMed

Werner, Theresa L; Sachdev, Jasgit; Swisher, Elizabeth M; Gutierrez, Martin; Kittaneh, Muaiad; Stein, Mark N; Xiong, Hao; Dunbar, Martin; Sullivan, Danielle; Komarnitsky, Philip; McKee, Mark; Tan, Antoinette R

2018-05-07

The poly(ADP-ribose) polymerase-1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended-release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib-ER up to 800 mg once daily or 600 mg twice daily. Dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28-day cycles). Seventy-one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single-dose veliparib-ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration-time curve compared with veliparib immediate-release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib-ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment-related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib-ER, versus veliparib-IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA-mutated breast cancers. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu; Das, Shiva; Gu, Lin

2015-12-01

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standardmore » 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.« less

Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors

PubMed Central

2014-01-01

Background Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Methods Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. Results MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. Conclusion MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity. Trial registration ClinicalTrials.gov: NCT00848718. PMID:24387695

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

PubMed Central

Mansky, Patrick J.; Sannes, Timothy S.; Johnson, Laura Lee; Blackman, Marc R.; Grem, Jean L.; Swain, Sandra M.; Monahan, Brian P.

2013-01-01

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone. PMID:24285980

A Phase 1 trial of the PARP inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer

PubMed Central

Liu, Joyce F.; Tolaney, Sara M.; Birrer, Michael; Fleming, Gini F.; Buss, Mary K.; Dahlberg, Suzanne E.; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A.

2014-01-01

Background PARP-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of VEGFR-1/2/3, and olaparib, a PARP-inhibitor (NCT01116648). Methods Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by RECIST 1.1 or met GCIG CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. Results 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 DLTs (1 grade 4 neutropenia ≥4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30mg daily; olaparib 400mg BID). The RP2D was cediranib 30mg daily and olaparib 200mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus SD >24 weeks) of 61%. None of the 7 evaluable breast cancer patients achieved clinical response; 2 patients had stable disease for >24 weeks. Interpretation The combination of cediranib and olaparib has hematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. PMID:23810467

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

PubMed Central

Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L.; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-01-01

Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. PMID:26926682

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML)

PubMed Central

Ravandi, Farhad; Gojo, Ivana; Patnaik, Mrinal M.; Minden, Mark D.; Kantarjian, Hagop; Johnson-Levonas, Amy O.; Fancourt, Craig; Lam, Raymond; Jones, Mary Beth; Knox, Clayton D.; Rose, Shelonitda; Patel, Payal Shah; Tibes, Raoul

2017-01-01

Objective Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML. Methods MK-8242 was dosed p.o. QD (30–250 mg) or BID (120–250 mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300 mg BID). Results 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250 mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210 mg BID or 300 mg BID (doses >300 mg not tested). Best responses were: 1/24 PR (11 weeks;120 mg QD, 7on/7off); 1/24 CRi (2 weeks;210 mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250 mg BID, 7on/7off). PK on Day7 at 210 mg BID revealed AUC0-12hr 8.7 μM*hr, Cmax 1.5 μM (n=5, Tmax, 2–6 hr), T1/2 7.9 hr, CLss/F 28.8 L/hr, and Vss/F 317 L. Conclusions The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML. PMID:27544076

Local allocation of lung donors results in transplanting lungs in lower priority transplant recipients.

PubMed

Russo, Mark J; Meltzer, David; Merlo, Aurelie; Johnson, Elizabeth; Shariati, Nazly M; Sonett, Joshua R; Gibbons, Robert

2013-04-01

Under the current lung allocation system, if organs are accepted for a candidate within the local donor service area (DSA), they are never offered to candidates at the broader regional level who are potentially more severely ill, even if the nonlocal candidate has a higher lung allocation score (LAS). The purpose of this study was to determine the frequency with which organs were allocated to a local lung recipient while a blood group-matched and size-matched candidate with a higher LAS existed in the same region. United Network for Organ Sharing (UNOS) provided deidentified patient-level data. The study population included all locally allocated organs for double-lung transplants (DLTs) performed in 2009 in the United States (n=580). All occurrences of an ABO blood group-matched, height-matched (±10 cm), double-lung candidate in the same region, with a higher LAS than the local candidate who actually received the organs, were calculated; these occurrences were termed events. In 2009, 3,454 events occurred when a local DLT recipient candidate received a DLT while a DLT candidate in the same region had a higher LAS. With a mean of 5.96 events per transplant, this impacted 480 (82.8%) of the 580 DLTs. Further, 555 (16.1%) of these events involved 1 (or more) of the 185 regional candidates who ultimately did not receive transplants and died while on the waiting list. This analysis suggests that the locally based lung allocation system results in a high frequency of events whereby an organ is allocated to a lower-priority candidate while an appropriately matched higher priority candidate exists regionally. Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Phonon-assisted changes in charge states of deep level defects in germanium

NASA Astrophysics Data System (ADS)

Markevich, A. V.; Litvinov, V. V.; Emtsev, V. V.; Markevich, V. P.; Peaker, A. R.

2006-04-01

Electronic processes associated with changes in the charge states of the vacancy-oxygen center (VO or A center) and vacancy-group-V-impurity atom (P, As, Sb or Bi) pairs (E centers) in irradiated germanium crystals have been studied using deep level transient spectroscopy (DLTS), high-resolution Laplace DLTS and Hall effect measurements. It is found that the electron emission and capture processes related to transitions between the doubly and the singly negatively charged states of the A center and the E centers in Ge are phonon-assisted, i.e., they are accompanied by significant vibrations and re-arrangements of atoms in the vicinity of the defects. Manifestations of the phonon involvements are: (i) temperature-dependent electron capture cross-sections which are well described in the frame of the multi-phonon-assisted capture model; (ii) large changes in entropy related to the ionization of the defects and, associated with these, temperature-dependent positions of energy levels; and (iii) electron emission via phonon-assisted tunneling upon the application of electric field. These effects have been considered in detail for the vacancy-oxygen and the vacancy-donor complexes. On the basis of a combined analysis of the electronic processes a configuration-coordinate diagram of the acceptor states of the A and E centers is plotted. It is found that changes in the entropy of ionization and the energy for electron emission for these traps follow the empirical Meyer-Neldel rule. A model based on multi-phonon-assisted carrier emission from defects is adapted for the explanation of the origin of this rule for the case of electronic processes in Ge.

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

PubMed

Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

PubMed

Chisholm, Julia C; Suvada, Jozef; Dunkel, Ira J; Casanova, Michela; Zhang, Weijiang; Ritchie, Natasha; Choi, YounJeong; Park, Jane; Das Thakur, Meghna; Simko, Stephen; Wan Rachel Tam, Nga; Ferrari, Andrea

2018-05-01

Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials. © 2018 Wiley Periodicals, Inc.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

PubMed

Manley, Peter E; Trippett, Tanya; Smith, Amy A; Macy, Margaret E; Leary, Sarah E S; Boklan, Jessica; Cohen, Kenneth J; Goldman, Stewart; Kilburn, Lindsay B; Dhall, Girish; Devin, Jeanne; Herzog, Cynthia E; Partap, Sonia; Fauchet, Floris; Badreddine, Emmy; Bernard, John P; Chi, Susan N

2018-05-11

This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m 2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m 2 ; the MTD was 30 mg/m 2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m 2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG. © 2018 Wiley Periodicals, Inc.

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.

PubMed

Liu, Joyce F; Tolaney, Sara M; Birrer, Michael; Fleming, Gini F; Buss, Mary K; Dahlberg, Suzanne E; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A

2013-09-01

Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ≥ 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

Double-lumen tubes and auto-PEEP during one-lung ventilation.

PubMed

Spaeth, J; Ott, M; Karzai, W; Grimm, A; Wirth, S; Schumann, S; Loop, T

2016-01-01

Double-lumen tubes (DLT) are routinely used to enable one-lung-ventilation (OLV) during thoracic anaesthesia. The flow-dependent resistance of the DLT's bronchial limb may be high as a result of its narrow inner diameter and length, and thus potentially contribute to an unintended increase in positive end-expiratory pressure (auto-PEEP). We therefore studied the impact of adult sized DLTs on the dynamic auto-PEEP during OLV. In this prospective clinical study, dynamic auto-PEEP was determined in 72 patients undergoing thoracic surgery, with right- and left-sided DLTs of various sizes. During OLV, air trapping was provoked by increasing inspiration to expiration ratio from 1:2 to 2:1 (five steps). Based on measured flow rate, airway pressure (Paw) and bronchial pressure (Pbronch), the pressure gradient across the DLT (ΔPDLT) and the total auto-PEEP in the respiratory system (i.e. the lungs, the DLT and the ventilator circuit) were determined. Subsequently the DLT's share in total auto-PEEP was calculated. ΔPDLT was 2.3 (0.7) cm H2O over the entire breathing cycle. At the shortest expiratory time the mean total auto-PEEP was 2.9 (1.5) cm H2O (range 0-5.9 cm H2O). The DLT caused 27 to 31% of the total auto-PEEP. Size and side of the DLT's bronchial limb did not impact auto-PEEP significantly. Although the DLT contributes to the overall auto-PEEP, its contribution is small and independent of size and side of the DLT's bronchial limb. The choice of DLT does not influence the risk of auto-PEEP during OLV to a clinically relevant extent. DRKS00005648. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Diffusivity of the double negatively charged mono-vacancy in silicon

NASA Astrophysics Data System (ADS)

Bhoodoo, Chidanand; Vines, Lasse; Monakhov, Edouard; Svensson, Bengt Gunnar

2017-05-01

Lightly-doped silicon (Si) samples of n-type conductivity have been irradiated with 2.0 MeV {{\\text{H}}+} ions at a temperature of 30 K and characterized in situ by deep level transient spectroscopy (DLTS) measurements using an on-line setup. Migration of the Si mono-vacancy in its double negative charge state (V 2-) starts to occur at temperatures above  ˜70 K and is monitored via trapping of V 2- by interstitial oxygen impurity atoms ({{\\text{O}}i} ), leading to the growth of the prominent vacancy-oxygen (V\\text{O} ) center. The V\\text{O} center gives rise to an acceptor level located at  ˜0.17 eV below the conduction band edge (E c ) and is readily detected by DLTS measurements. Post-irradiation isothermal anneals at temperatures in the range of 70 to 90 K reveal first-order kinetics for the reaction {{V}2-}+{{\\text{O}}i}\\to V\\text{O} ≤ft(+ 2{{e}-}\\right) in both Czochralski-grown and Float-zone samples subjected to low fluences of {{\\text{H}}+} ions, i.e. the irradiation-induced V concentration is dilute (≤slant 1013 cm-3). On the basis of these kinetics data and the content of {{\\text{O}}i} , the diffusivity of V 2- can be determined quantitatively and is found to exhibit an activation energy for migration of  ˜0.18 eV with a pre-exponential factor of  ˜4× {{10}-3} cm2 s-1. The latter value evidences a simple jump process without any entropy effects for the motion of V 2-. No deep level in the bandgap to be associated with V 2- is observed but the results suggest that the level is situated deeper than  ˜0.19 eV below E c , corroborating results reported previously in the literature.

Interface traps contribution on transport mechanisms under illumination in metal-oxide-semiconductor structures based on silicon nanocrystals

NASA Astrophysics Data System (ADS)

Chatbouri, S.; Troudi, M.; Kalboussi, A.; Souifi, A.

2018-02-01

The transport phenomena in metal-oxide-semiconductor (MOS) structures having silicon nanocrystals (Si-NCs) inside the dielectric layer have been investigated, in dark condition and under visible illumination. At first, using deep-level transient spectroscopy (DLTS), we find the presence of series electron traps having very close energy levels (comprised between 0.28 and 0.45 eV) for ours devices (with/without Si-NCs). And a single peak appears at low temperature only for MOS with Si-NCs related to Si-NCs DLTS response. In dark condition, the conduction mechanism is dominated by the thermionic fast emission/capture of charge carriers from the highly doped polysilicon layer to Si-substrate through interface trap states for MOS without Si-NCs. The tunneling of charge carriers from highly poly-Si to Si substrate trough the trapping/detrapping mechanism in the Si-NCs, at low temperature, contributed to the conduction mechanism for MOS with Si-NCs. The light effect on transport mechanisms has been investigated using current-voltage ( I- V), and high frequency capacitance-voltage ( C- V) methods. We have been marked the photoactive trap effect in inversion zone at room temperature in I- V characteristics, which confirm the contribution of photo-generated charge on the transport mechanisms from highly poly-Si to Si substrate trough the photo-trapping/detrapping mechanism in the Si-NCs and interfaces traps levels. These results have been confirmed by an increasing about 10 pF in capacity's values for the C- V characteristics of MOS with Si-NCs, in the inversion region for inverse high voltage applied under photoexcitation at low temperature. These results are helpful to understand the principle of charge transport in dark condition and under illumination, of MOS structures having Si-NCs in the SiO x = 1.5 oxide matrix.

Lifetime degradation of n-type Czochralski silicon after hydrogenation

NASA Astrophysics Data System (ADS)

Vaqueiro-Contreras, M.; Markevich, V. P.; Mullins, J.; Halsall, M. P.; Murin, L. I.; Falster, R.; Binns, J.; Coutinho, J.; Peaker, A. R.

2018-04-01

Hydrogen plays an important role in the passivation of interface states in silicon-based metal-oxide semiconductor technologies and passivation of surface and interface states in solar silicon. We have shown recently [Vaqueiro-Contreras et al., Phys. Status Solidi RRL 11, 1700133 (2017)] that hydrogenation of n-type silicon slices containing relatively large concentrations of carbon and oxygen impurity atoms {[Cs] ≥ 1 × 1016 cm-3 and [Oi] ≥ 1017 cm-3} can produce a family of C-O-H defects, which act as powerful recombination centres reducing the minority carrier lifetime. In this work, evidence of the silicon's lifetime deterioration after hydrogen injection from SiNx coating, which is widely used in solar cell manufacturing, has been obtained from microwave photoconductance decay measurements. We have characterised the hydrogenation induced deep level defects in n-type Czochralski-grown Si samples through a series of deep level transient spectroscopy (DLTS), minority carrier transient spectroscopy (MCTS), and high-resolution Laplace DLTS/MCTS measurements. It has been found that along with the hydrogen-related hole traps, H1 and H2, in the lower half of the gap reported by us previously, hydrogenation gives rise to two electron traps, E1 and E2, in the upper half of the gap. The activation energies for electron emission from the E1 and E2 trap levels have been determined as 0.12, and 0.14 eV, respectively. We argue that the E1/H1 and E2/H2 pairs of electron/hole traps are related to two energy levels of two complexes, each incorporating carbon, oxygen, and hydrogen atoms. Our results show that the detrimental effect of the C-O-H defects on the minority carrier lifetime in n-type Si:O + C materials can be very significant, and the carbon concentration in Czochralski-grown silicon is a key parameter in the formation of the recombination centers.

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org; Won, Minhee; Wen, Patrick Y.

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established dailymore » dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.« less

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Phase I Dose Escalation Trial of Vandetanib With Fractionated Radiosurgery in Patients With Recurrent Malignant Gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fields, Emma C.; Damek, Denise; Gaspar, Laurie E.

2012-01-01

Purpose: To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas. Methods and Materials: Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor {<=}6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose ofmore » 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity. Results: Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease. Conclusion: The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.« less

Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

PubMed

Abu-Khalaf, Maysa M; Baumgart, Megan A; Gettinger, Scott N; Doddamane, Indukala; Tuck, David P; Hou, Shihe; Chen, Nianhang; Sullivan, Catherine; Lezon-Geyda, Kimberly; Zelterman, Daniel; Hatzis, Christos; Deshpande, Hari; Digiovanna, Michael P; Azodi, Masoud; Schwartz, Peter E; Harris, Lyndsay N

2015-06-01

The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated. A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography. Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors. © 2015 American Cancer Society.

A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.

PubMed

Bedard, Philippe L; Tabernero, Josep; Janku, Filip; Wainberg, Zev A; Paz-Ares, Luis; Vansteenkiste, Johan; Van Cutsem, Eric; Pérez-García, José; Stathis, Anastasios; Britten, Carolyn D; Le, Ngocdiep; Carter, Kirsten; Demanse, David; Csonka, Denes; Peters, Malte; Zubel, Angela; Nauwelaerts, Heidi; Sessa, Cristiana

2015-02-15

MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. ©2014 American Association for Cancer Research.

Cell performance and defect behavior in proton-irradiated lithium-counterdoped n(+)p silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Stupica, J. W.; Swartz, C. K.; Goradia, C.

1986-01-01

Lithium-counterdoped n(+)p silicon solar cells were irradiated by 10-MeV protons, and their performance was determined as a function of fluence. It was found that the cell with the highest lithium concentration exhibited the higher radiation resistance. Deep-level transient spectroscopy studies of deep-level defects were used to identify two lithium-related defects. Defect energy levels obtained after the present 10-MeV irradiations were found to be markedly different than those observed after previous 1-MeV electron irradiations. However, the present DLTS data are consistent with previous suggestion by Weinberg et al. (1984) of a lithium-oxygen interaction which tends to inhibit formation of an interstitial boron-oxygen defect.

Point defects in CdTe xSe 1-x crystals grown from a Te-rich solution for applications in detecting radiation

DOE PAGES

Gul, R.; Roy, U. N.; Bolotnikov, A. E.; ...

2015-04-15

We investigated cadmium telluride selenide (CdTeSe) crystals, newly grown by the Traveling Heater Method (THM), for the presence and abundance of point defects. Deep Level Transient spectroscopy (I-DLTS) was used to determine the energies of the traps, their capture cross sections, and densities. The bias across the detectors was varied from (1–30) V. Four types of point defects were identified, ranging from 10 meV to 0.35 eV. Two dominant traps at energies of 0.18 eV and 0.14 eV were studied in depth. Cd vacancies are found at lower concentrations than other point defects present in the material.

Temperature coefficients and radiation induced DLTS spectra of MOCVD grown n(+)p InP solar cells

NASA Technical Reports Server (NTRS)

Walters, Robert J.; Statler, Richard L.; Summers, Geoffrey P.

1991-01-01

The effects of temperature and radiation on n(+)p InP solar cells and mesa diodes grown by metallorganic chemical vapor deposition (MOCVD) were studied. It was shown that MOCVD is capable of consistently producing good quality InP solar cells with Eff greater than 19 percent which display excellent radiation resistance due to minority carrier injection and thermal annealing. It was also shown that universal predictions of InP device performance based on measurements of a small group of test samples can be expected to be quite accurate, and that the degradation of an InP device due to any incident particle spectrum should be predictable from a measurement following a single low energy proton irradiation.

Effects of Iron Contamination and Hydrogen Passivation on the Electrical Properties of Oxygen Precipitates in CZ-Si

NASA Astrophysics Data System (ADS)

Li, Jiyang; Song, Lihui; Yu, Xuegong; Yang, Deren

2018-04-01

Oxygen precipitates (OPs) are unavoidably formed in Czochralski silicon (CZ-Si) containing relatively high concentrations of oxygen. The recombination behavior of such defects is also vital for bulk devices like solar cells as they can reduce the minority carrier lifetime and degrade the cell performance. In our experiments, the characteristics of oxygen precipitation in n-type CZ-Si are systematically investigated by means of Fourier transform infrared spectroscopy (FTIR), deep level transient spectroscopy (DLTS) and electron beam induced current (EBIC). It is found that the iron contamination in n-type CZ-Si can strongly influence the OPs generation and their electrical properties, whereas the hydrogen passivation can effectively reduce the recombination activity of OPs.

Deep levels in osmium doped p-type GaAs grown by metal organic chemical vapor deposition

NASA Astrophysics Data System (ADS)

Iqbal, M. Zafar; Majid, A.; Dadgar, A.; Bimberg, D.

2005-06-01

Results of a preliminary study on deep level transient spectroscopy (DLTS) investigations of osmium (Os) impurity in p-type GaAs, introduced in situ during MOCVD crystal growth, are reported for the first time. Os is clearly shown to introduce two prominent deep levels in the lower half-bandgap of GaAs at energy positions Ev + 0.42 eV (OsA) and Ev + 0.72 eV (OsB). A minority-carrier emitting defect feature observed in the upper half-bandgap is shown to consist of a band of Os-related deep levels with a concentration significantly higher than that of the majority carrier emitting deep levels. Detailed data on the emission rate signatures and related parameters of the Os-related deep levels are reported.

Formation of copper precipitates in silicon

NASA Astrophysics Data System (ADS)

Flink, Christoph; Feick, Henning; McHugo, Scott A.; Mohammed, Amna; Seifert, Winfried; Hieslmair, Henry; Heiser, Thomas; Istratov, Andrei A.; Weber, Eicke R.

1999-12-01

The formation of copper precipitates in silicon was studied after high-temperature intentional contamination of p- and n-type FZ and Cz-grown silicon and quench to room temperature. With the Transient Ion Drift (TID) technique on p-type silicon a critical Fermi level position at EC-0.2 eV was found. Only if the Fermi level position, which is determined by the concentrations of the acceptors and the copper donors, surpasses this critical value precipitation takes place. If the Fermi level is below this level the supersaturated interstitial copper diffuses out. An electrostatic precipitation model is introduced that correlates the observed precipitation behavior with the electrical activity of the copper precipitates as detected with Deep Level Transient Spectroscopy (DLTS) on n-type and with Minority Carrier Transient Spectroscopy (MCTS) on p-type silicon.

Electron paramagnetic resonance of deep boron in silicon carbide

NASA Astrophysics Data System (ADS)

Baranov, P. G.; Mokhov, E. N.

1996-04-01

In this article we report the first EPR observation of deep boron centres in silicon carbide. A direct identification of the boron atom involved in the defect centre, considered as deep boron, has been established by the presence of a hyperfine interaction with 0268-1242/11/4/005/img1 and 0268-1242/11/4/005/img2 nuclei in isotope-enriched 6H-SiC:B crystals. Deep boron centres were shown from EPR spectra to have axial symmetry along the hexagonal axis. A correspondence between the EPR spectra and the luminescence, ODMR and DLTS spectra of deep boron centres has been indicated. The structural model for a deep boron centre as a boron - vacancy pair is presented and the evidence for bistable behaviour of deep boron centres is discussed.

Electrically Active Defects In Solar Cells Based On Amorphous Silicon/Crystalline Silicon Heterojunction After Irradiation By Heavy Xe Ions

NASA Astrophysics Data System (ADS)

Harmatha, Ladislav; Mikolášek, Miroslav; Stuchlíková, L'ubica; Kósa, Arpád; Žiška, Milan; Hrubčín, Ladislav; Skuratov, Vladimir A.

2015-11-01

The contribution is focused on the diagnostics of structures with a heterojunction between amorphous and crystalline silicon prepared by HIT (Heterojunction with an Intrinsic Thin layer) technology. The samples were irradiated by Xe ions with energy 167 MeV and doses from 5 × 108 cm-2 to 5 × 1010 cm-2. Radiation defects induced in the bulk of Si and at the hydrogenated amorphous silicon and crystalline silicon (a-Si:H/c-Si) interface were identified by Deep Level Transient Spectroscopy (DLTS). Radiation induced A-centre traps, boron vacancy traps and different types of divacancies with a high value of activation energy were observed. With an increased fluence of heavy ions the nature and density of the radiation induced defects was changed.

A phase I study of cabazitaxel in combination with platinum and 5-fluorouracil (PF) in locally advanced squamous cell carcinoma of head and neck (LA-SCCHN).

PubMed

Camille, Nadia; Rozehnal, John; Roy, Elizabeth; Uczkowski, Dariusz; Olson, Ashely; Genden, Eric; Teng, Marita; Bakst, Richard; Gupta, Vishal; Posner, Marshall; Misiukiewicz, Krzysztof

2017-08-01

There is a clinical need to improve outcomes for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), especially in Human Papilloma Virus (HPV) negative and HPV positive subtypes with a significant history of tobacco use. In animal models bearing SCCHN, Cabazitaxel showed an excellent response rate compared to docetaxel and might prove useful in treatment of patients. The primary objective of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of cabazitaxel when combined with cisplatin and 5-fluorouracil (PF) in induction chemotherapy (IC) for patients with SCCHN. Cabazitaxel-PF IC administered in 3 cycles (each 21 days) followed by concurrent chemoradiation (CRT) or surgery has been evaluated to assess overall response rate (ORR) and progression-free survival (PFS) in this population. This phase I study employed a standard 3+3 design. DLT was defined as grade 4 or 5 toxicity or grade 3 toxicity lasting >7days. Out of 40 consented patients with stage IV, curable, previously untreated, LA-SCHHN and poor prognosis, 35 (32M, 3F) were enrolled and evaluated for toxicity: 19 oropharynx, 10 larynx, 2 oral cancer, 1 nasopharynx and 3 hypopharynx. Five dose levels of cabazitaxel (10, 12.5, 15, 17.5 and 20mg/m 2 ) were tested in combination with cisplatin 100mg/m 2 and 5-fluorouracil (5-FU) 800mg/m 2 /d×4days. Dose escalation for cabazitaxel was terminated upon the occurrences of 2 DLTs and the establishment of MTD. Cabazitaxel was then further escalated with cisplatin 75mg/m 2 and 5-FU 800mg/m 2 /d×4days in the subsequent 3 dose levels (17.5, 20 and 22.5mg/m 2 ). In the expansion cohort, 9 patients were enrolled at the 22.5mg/m 2 dose level. Following 3 cycles of IC, patients were evaluated for clinical, radiographic, and pathologic response to cabazitaxel-PF before beginning CRT or surgery. There were two DLTs (grade 4 hyperuricemia; neutropenic fever, sepsis, and grade 4 thrombocytopenia) among 2 patients in cohort 5 at the dose of 20mg/m 2 of cabazitaxel. There were no DLTs reported with cohorts using a lower dose of cisplatin, even in the expansion cohort. The study was stopped at the dose of 22.5mg/m 2 in accordance with the initial study design. With 33 evaluable patients for response, the Overall Response Rate (ORR) rate was 57.6%: 9.1% Complete Responses (CR) and 48.5% Partial Responses (PR) were noted. The recommended phase II dose for cabazitaxel in combination with cisplatin 75mg/m 2 and 5-FU 800mg/m 2 /d×4days is 22.5mg/m 2 and for cisplatin 100mg/m 2 and 5-FU 800mg/m 2 /d×4days is 17.5mg/m 2 . With a median follow-up of 39months, PFS for the entire non-metastatic population at 3years was approximately 58%. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Phase I Study of Triapine® in Combination with Doxorubicin in Patients with Advanced Solid Tumors

PubMed Central

Schelman, William R.; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M.; Ivy, Percy; Wilding, George; Traynor, Anne M.

2011-01-01

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Study Design Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Results Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 mg/m2 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Conclusions Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on days 1-4 of a 21 day cycle. PMID:19082825

A phase I study of Triapine in combination with doxorubicin in patients with advanced solid tumors.

PubMed

Schelman, William R; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M; Ivy, Percy; Wilding, George; Traynor, Anne M

2009-05-01

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

PubMed

O'Reilly, Eileen M; Lee, Jonathan W; Lowery, Maeve A; Capanu, Marinela; Stadler, Zsofia K; Moore, Malcolm J; Dhani, Neesha; Kindler, Hedy L; Estrella, Hayley; Maynard, Hannah; Golan, Talia; Segal, Amiel; Salo-Mullen, Erin E; Yu, Kenneth H; Epstein, Andrew S; Segal, Michal; Brenner, Robin; Do, Richard K; Chen, Alice P; Tang, Laura H; Kelsen, David P

2018-04-01

A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Gemcitabine and cisplatin were dosed at 600 and 25 mg/m 2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society. © 2018 American Cancer Society.

Electrical and structural characterizations of crystallized Al{sub 2}O{sub 3}/GaN interfaces formed by in situ metalorganic chemical vapor deposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, X., E-mail: xliu@ece.ucsb.edu; Yeluri, R.; Kim, J.

2016-01-07

Al{sub 2}O{sub 3} films were grown in situ by metalorganic chemical vapor deposition at 900 °C on GaN of both Ga- and N-face polarities. High-resolution transmission electron microscopy revealed that the Al{sub 2}O{sub 3} films were crystalline and primarily γ-phase. The Al{sub 2}O{sub 3}/Ga-GaN and Al{sub 2}O{sub 3}/N-GaN interfaces were both atomically sharp, and the latter further exhibited a biatomic step feature. The corresponding current-voltage (J-V) characteristics were measured on a metal-Al{sub 2}O{sub 3}-semiconductor capacitor (MOSCAP) structure. The leakage current was very high when the Al{sub 2}O{sub 3} thickness was comparable with the size of the crystalline defects, but was suppressedmore » to the order of 1 × 10{sup −8} A/cm{sup 2} with larger Al{sub 2}O{sub 3} thicknesses. The interface states densities (D{sub it}) were measured on the same MOSCAPs by using combined ultraviolet (UV)-assisted capacitance-voltage (C-V), constant capacitance deep level transient spectroscopy (CC-DLTS), and constant capacitance deep level optical spectroscopy (CC-DLOS) techniques. The average D{sub it} measured by CC-DLTS and CC-DLOS were 6.6 × 10{sup 12} and 8.8 × 10{sup 12} cm{sup −2} eV{sup −1} for Al{sub 2}O{sub 3}/Ga-GaN and 8.6 × 10{sup 12} and 8.6 × 10{sup 12 }cm{sup −2} eV{sup −1} for Al{sub 2}O{sub 3}/N-GaN, respectively. The possible origins of the positive (negative) polarization compensation charges in Al{sub 2}O{sub 3}/Ga-GaN (Al{sub 2}O{sub 3}/N-GaN), including the filling of interface states and the existence of structure defects and impurities in the Al{sub 2}O{sub 3} layer, were discussed in accordance with the experimental results and relevant studies in the literature.« less

Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma.

PubMed

Iwamoto, Kana; Ishihara, Hiroki; Takagi, Toshio; Kondo, Tsunenori; Yoshida, Kazuhiko; Iizuka, Junpei; Tanabe, Kazunari

2018-04-23

Sunitinib treatment with a 2-week-on/1-week-off schedule (Schedule 2/1) is a common alternative regimen with high relative dose intensity (RDI) and superior tolerability for patients with metastatic renal cell carcinoma (mRCC). The prognostic impact of RDI is reported only in 4-week-on/2-week-off or mixed regimens. Herein, we evaluated the prognostic impact of RDI during early-phase sunitinib treatment using Schedule 2/1. Seventy-four patients who received first-line sunitinib treatment using Schedule 2/1 were evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). We assessed RDI within the initial two cycles (2c-RDI), and its prognostic impact. Predictive factors for 2c-RDI deterioration were also evaluated. The cut-off value of 2c-RDI was set at 65%. Based on this cut-off, 31 patients (42.0%) were classified into the low 2c-RDI group (< 65%). PFS and OS were significantly shorter in the low-2c-RDI patients, compared with the high 2c-RDI patients (median PFS: 6.15 vs. 18.4 months, p = 0.0005; OS 11.0 vs. 39.3 months, p = 0.0002). Furthermore, multivariate analyses showed that the development of dose-limiting toxicities (DLTs) within the initial two cycles, as well as low initial dose, were independent factors for low 2c-RDI (DLTs: OR 18.6, 95% CI 3.27-105.30, p = 0.0010; initial dose: OR 9.26, 95% CI 1.42-60.40, p = 0.020). The most common adverse event was thrombocytopenia (any grade: 24.3%; grade ≥ 3: 8.1%). More than 65% of 2c-RDI should be maintained for optimal therapeutic effect of sunitinib treatment using Schedule 2/1. To achieve the appropriate 2c-RDI, careful follow-up for patient tolerability is needed to avoid early DLT development.

A simple blind placement of the left-sided double-lumen tubes.

PubMed

Zong, Zhi Jun; Shen, Qi Ying; Lu, Yao; Li, Yuan Hai

2016-11-01

One-lung ventilation (OLV) has been commonly provided by using a double-lumen tube (DLT). Previous reports have indicated the high incidence of inappropriate DLT positioning in conventional maneuvers.After obtaining approval from the medical ethics committee of First Affiliated Hospital of Anhui Medical University and written consent from patients, 88 adult patients belonging to American society of anesthesiologists (ASA) physical status grade I or II, and undergoing elective thoracic surgery requiring a left-side DLT for OLV were enrolled in this prospective, single-blind, randomized controlled study. Patients were randomly allocated to 1 of 2 groups: simple maneuver group or conventional maneuver group. The simple maneuver is a method that relies on partially inflating the bronchial balloon and recreating the effect of a carinal hook on the DLTs to give an idea of orientation and depth. After the induction of anesthesia the patients were intubated with a left-sided Robertshaw DLT using one of the 2 intubation techniques. After intubation of each DLT, an anesthesiologist used flexible bronchoscopy to evaluate the patient while the patient lay in a supine position. The number of optimal position and the time required to place DLT in correct position were recorded.Time for the intubation of DLT took 100 ± 16.2 seconds (mean ± SD) in simple maneuver group and 95.1 ± 20.8 seconds in conventional maneuver group. The difference was not statistically significant (P = 0.221). Time for fiberoptic bronchoscope (FOB) took 22 ± 4.8 seconds in simple maneuver group and was statistically faster than that in conventional maneuver group (43.6 ± 23.7 seconds, P < 0.001). Nearly 98% of the 44 intubations in simple maneuver group were considered as in optimal position while only 52% of the 44 intubations in conventional maneuver group were in optimal position, and the difference was statistically significant (P < 0.001).This simple maneuver is more rapid and more accurate to position left-sided DLTs, it may be substituted for FOB during positioning of a left-sided DLT in condition that FOB is unavailable or inapplicable.

Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.

PubMed

Atkins, Michael B; Hodi, F Stephen; Thompson, John A; McDermott, David F; Hwu, Wen-Jen; Lawrence, Donald P; Dawson, Nancy A; Wong, Deborah J; Bhatia, Shailender; James, Marihella; Jain, Lokesh; Robey, Seth; Shu, Xinxin; Homet Moreno, Blanca; Perini, Rodolfo F; Choueiri, Toni K; Ribas, Antoni

2018-04-15

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR . ©2018 American Association for Cancer Research.

Root causes investigation of catastrophic optical bulk damage in high-power InGaAs-AlGaAs strained QW lasers

NASA Astrophysics Data System (ADS)

Sin, Yongkun; Lingley, Zachary; Ayvazian, Talin; Brodie, Miles; Ives, Neil

2018-02-01

High-power single-mode (SM) and multi-mode (MM) InGaAs-AlGaAs strained quantum well (QW) lasers are critical components for both terrestrial and space satellite communications systems. Since these lasers predominantly fail by catastrophic and sudden degradation due to COD, it is especially crucial for space satellite applications to investigate reliability, failure modes, and degradation mechanisms of these lasers. Our group reported a new failure mode in MM and SM InGaAs-AlGaAs strained QW lasers in 2009 and 2016, respectively. Our group also reported in 2017 that bulk failure due to catastrophic optical bulk damage (COBD) is the dominant failure mode of both SM and MM lasers that were subject to long-term life-tests. For the present study, we report root causes investigation of COBD by performing long-term lifetests followed by failure mode analysis (FMA) using various micro-analytical techniques including electron beam induced current (EBIC), time-resolved electroluminescence (EL), focused ion beam (FIB), high-resolution transmission electron microscopy (TEM), and deep level transient spectroscopy (DLTS). Our life-tests with accumulated test hours of over 25,000 hours for SM lasers and over 35,000 hours for MM lasers generated a number of COBD failures with various failure times. EBIC techniques were employed to study dark line defects (DLDs) generated in SM COBD failures stressed under different test conditions. FIB and high-resolution TEM were employed to prepare cross sectional and plan view TEM specimens to study DLD areas (dislocations) in post-aged SM lasers. Time-resolved EL techniques were employed to study initiation and progressions of dark spots and dark lines in real time as MM lasers were aged. Lastly, to investigate precursor signatures of failure and degradation mechanisms responsible for COBD in both SM and MM lasers, we employed DLTS techniques to study a role that electron traps (non-radiative recombination centers) play in degradation of these lasers. Our in-depth root causes investigation results are reported.

Phase I Trial of Anti-MET Monoclonal Antibody in MET-Overexpressed Refractory Cancer.

PubMed

Lee, Jeeyun; Kim, Seung Tae; Park, Sungju; Lee, Sujin; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Ahn, Hongmo; Bok, Haesook; Kim, Kyoung-Mee; Ahn, Myung Ju; Kang, Won Ki; Park, Young Suk

2018-06-01

Samsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas. SAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound. Sixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II. We successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg. Copyright © 2018 Elsevier Inc. All rights reserved.

Defect study in ZnO related structures—A multi-spectroscopic approach

NASA Astrophysics Data System (ADS)

Ling, C. C.; Cheung, C. K.; Gu, Q. L.; Dai, X. M.; Xu, S. J.; Zhu, C. Y.; Luo, J. M.; Zhu, C. Y.; Tam, K. H.; Djurišić, A. B.; Beling, C. D.; Fung, S.; Lu, L. W.; Brauer, G.; Anwand, W.; Skorupa, W.; Ong, H. C.

2008-10-01

ZnO has attracted a great deal of attention in recent years because of its potential applications for fabricating optoelectronic devices. Using a multi-spectroscopic approach including positron annihilation spectroscopy (PAS), deep level transient spectroscopy (DLTS), photoluminescence (PL) and X-ray photoelectron spectroscopy (XPS), we have studied the two observed phenomena from ZnO related structures. They namely included the H 2O 2 pre-treatment induced ohmic to rectifying contact conversion on Au/ n-ZnO contact and the p-type doping by nitrogen ion implantation. The aim of the studies was to offering comprehensive views as to how the defects influenced the structures electrical and optical properties of the structures. It was also shown that PAS measurement using the monoenergetic positron beam could offer valuable information of vacancy type defects in the vertical ZnO nanorod array structure.

Development of high-efficiency solar cells on silicon web

NASA Technical Reports Server (NTRS)

Meier, D. L.; Greggi, J.; Rai-Choudhury, P.

1986-01-01

Work is reported aimed at identifying and reducing sources of carrier recombination both in the starting web silicon material and in the processed cells. Cross-sectional transmission electron microscopy measurements of several web cells were made and analyzed. The effect of the heavily twinned region on cell efficiency was modeled, and the modeling results compared to measured values for processed cells. The effects of low energy, high dose hydrogen ion implantation on cell efficiency and diffusion length were examined. Cells were fabricated from web silicon known to have a high diffusion length, with a new double layer antireflection coating being applied to these cells. A new contact system, to be used with oxide passivated cells and which greatly reduces the area of contact between metal and silicon, was designed. The application of DLTS measurements to beveled samples was further investigated.

Development of high-efficiency solar cells on silicon web

NASA Technical Reports Server (NTRS)

Meier, D. L.

1986-01-01

Achievement of higher efficiency cells by directing efforts toward identifying carrier loss mechanisms; design of cell structures; and development of processing techniques are described. Use of techniques such as deep-level transient spectroscopy (DLTS), laser-beam-induced current (LBIC), and transmission electron microscopy (TEM) indicated that dislocations in web material rather than twin planes were primarily responsible for limiting diffusion lengths in the web. Lifetimes and cell efficiencies can be improved from 19 to 120 microns, and 8 to 10.3% (no AR), respectively, by implanting hydrogen at 1500 eV and a beam current density of 2.0 mA/sq cm. Some of the processing improvements included use of a double-layer AR coating (ZnS and MgF2) and an addition of an aluminum back surface reflectors. Cells of more than 16% efficiency were achieved.

Non-Ideal Properties of Gallium Nitride Based Light-Emitting Diodes

NASA Astrophysics Data System (ADS)

Shan, Qifeng

The spectacular development of gallium nitride (GaN) based light-emitting diodes (LEDs) in recent years foreshadows a new era for lighting. There are still several non-ideal properties of GaN based LEDs that hinder their widespread applications. This dissertation studies these non-ideal properties including the large reverse leakage current, large subthreshold forward leakage current, an undesired parasitic cyan luminescence and high-concentration deep levels in GaInN blue LEDs. This dissertation also studies the thermal properties of GaInN LEDs. Chapter 1 gives a brief introduction of non-ideal properties of GaN based LEDs. The leakage current of GaN based LEDs, defects in epitaxially grown GaN devices, and doping problems of p-type GaN materials are discussed. The transient junction temperature measurement technique for GaN based LEDs is introduced. The leakage current of an LED includes the subthreshold forward leakage current and the reverse leakage current. The leakage current of GaN based LEDs affects the reliability, electrostatic discharge resilience, and sub-threshold power consumption. In Chapter 2, the reverse leakage current of a GaInN LED is analyzed by temperaturedependent current-voltage measurements. At low temperature, the reverse leakage current is attributed to the variable-range-hopping conduction. At high temperature, the reverse leakage current is attributed to a thermally-assisted multi-step tunneling. The thermal activation energies (95 meV ~ 162 meV), extracted from the Arrhenius plot for the reverse current in the high-temperature range, indicate a thermally activated tunneling process. Additional room-temperature capacitance-voltage (C-V) measurements are performed to obtain information on the depletion width and doping concentration of the LED. The average internal electric field is estimated by the C-V measurements. The strong internal electric field enhances the thermal emission of electrons in the thermally-assisted multi-step tunneling process. Another problem of GaInN blue LEDs is the undesired parasitic cyan emission band. The undesired parasitic emission band strongly influence the electrical and optical properties of GaInN blue LEDs including the subthreshold forward leakage current and the color purity of the emission. In Chapter 3 , GaInN blue LEDs emitting at 445 nm with a parasitic cyan (blue-green) emission band (480 nm), which dominates the emission spectrum at low injection current, are analyzed. Photoluminescence using resonant optical excitation shows that the cyan emission originates from the active region of the LED. The current- and excitation-density-dependent blue-to-cyan intensity ratio reveals that the cyan emission is due to a transition from the conduction band to a Mg acceptor having diffused into the last-grown quantum well of the active region. The Mg in the active region provides an additional carrier-transport path, and therefore can explain the high subthreshold forward leakage current that is measured in these LEDs. Deep levels in GaN-based materials strongly affect the electrical and optical properties of GaN-based LEDs. Chapter 4 describes the basic principle and the setup of a deep-level transient spectroscopy (DLTS) measurement system. This DLTS system is used to determine the concentration and thermal activation energy of deep levels in the depletion region of the GaInN LED. Two types of hole traps in the n-type side of the depletion region are observed in the DLTS measurement. The thermal activation energies of these two types of hole traps are compared with the results reported in literature. The hole trap associated with the major DLTS peak with a thermal activation energy of 0.80 eV is presumably related to the “yellow luminescence band”. Self-heating of LEDs is an important issue that affects the efficiency and reliability. In Chapter 5, the thermal properties, including thermal time constants, of GaN LEDs are analyzed. The transient-junction-temperature behavior of unpackaged LED chips is described by a single time constant, which is the product of a thermal resistance Rth and a thermal capacitance Cth. Furthermore, a multistage RthCth thermal model for packaged LEDs is developed. The transient response of the junction temperature of LEDs after the power is switched on or switched off can be described by a multi-exponential function. Each time constant of this function is approximately the product of a thermal resistance, Rth, and a thermal capacitance, Cth. The transient junction temperature after the power is switched off is measured for a high-power flip-chip LED by the forward-voltage method. A two-stage RthCth model is used to analyze the thermal properties of the packaged LED. Two time constants, 2.72 ms and 18.7 ms are extracted from the junction temperature decay measurement and attributed to the thermal time constant of the LED GaN / sapphire chip and LED Si submount, respectively.

Titanium in silicon as a deep level impurity

NASA Technical Reports Server (NTRS)

Chen, J.-W.; Milnes, A. G.; Rohatgi, A.

1979-01-01

Titanium inserted in silicon by diffusion or during Czochralski ingot growth is electrically active to a concentration level of about 4 x 10 to the 14th per cu cm. It is reported that Hall measurements after diffusion show conversion of lightly doped p-type Si to n-type due to a Ti donor level at E sub c -0.22 eV. In addition, in DLTS measurements of n(+)p structures this level shows as an electron (minority carrier) trap at E sub c -0.26 eV with an electron capture cross section of about 3 x 10 to the -15th per sq cm at 300 K. Finally, a Ti electrically active concentration of about 1.35 x 10 to the 13th per cu cm in p type Si results in a minority carrier (electron) lifetime of 50 nsec at 300 K.

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer.

PubMed

Sym, Sun Jin; Hong, Junsik; Jung, Minkyu; Park, Jinny; Cho, Eun Kyung; Lee, Woon Ki; Chung, Min; Kim, Hyung-Sik; Lee, Jae Hoon; Shin, Dong Bok

2012-08-01

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC). Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0-2, were enrolled in this study. A fixed dose of epirubicin (50 mg/m(2)) and oxaliplatin (130 mg/m(2)) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1-14. The S-1 dose was escalated according to the following schedule: level I, 35 mg/m(2); level II, 40 mg/m(2); level III, 45 mg/m(2); Level IV, 50 mg/m(2). Each cycle was repeated every 21 days. DLTs were evaluated during the first two cycles of treatment. Nineteen patients with a median age of 53 years (range, 40-71 years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5 days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5 % (95 % confidence interval (CI), 13.3-66.6 %). The median progression-free survival and overall survival of all patients was 6.8 months (95 % CI, 1.4-9.5 months) and 13.3 months (95 % CI, 1.9-24.6 months), respectively. The RD of the EOS regimen in patients with previously untreated AGC was 50 mg/m(2) of epirubicin and 130 mg/m(2) of oxaliplatin on day 1, with administration of 40 mg/m(2) of S-1 twice a day on days 1-14 for each 21-day cycle. The EOS regimen described produced promising results.

Defects and annealing studies in 1-Me electron irradiated (AlGa)As-GaAs solar cells

NASA Technical Reports Server (NTRS)

Li, S. S.; Wang, W. L.; Loo, R. Y.; Rahilly, W. P.

1982-01-01

The deep-level defects and recombination mechanisms in the one-MeV electron irradiated (AlGa)As-GaAs solar cells under various irradiation and annealing conditions are discussed. Deep-level transient spectroscopy (DLTS) and capacitance-voltage (CV) techniques were used to determine the defect and recombination parameters such as energy levels and defect density, carrier capture cross sections and lifetimes for both electron and hole traps as well as hole diffusion lengths in these electron irradiated GaAs solar cells. GaAs solar cells used in this study were prepared by the infinite solution melt liquid phase epitaxial (LPE) technique at Hughes Research Lab., with (Al0.9Ga0.1)-As window layer, Be-diffused p-GaAs layer on Sn-doped n-GaAs or undoped n-GaAs active layer grown on n(+)-GaAs substrate. Mesa structure with area of 5.86x1000 sq cm was fabricated. Three different irradiation and annealing experiments were performed on these solar cells.

Effect of combined platinum and electron on the temperature dependence of forward voltage in fast recovery diode

NASA Astrophysics Data System (ADS)

Jia, Yun-Peng; Zhao, Bao; Yang, Fei; Wu, Yu; Zhou, Xuan; Li, Zhe; Tan, Jian

2015-12-01

The temperature dependences of forward voltage drop (VF) of the fast recovery diodes (FRDs) are remarkably influenced by different lifetime controlled treatments. In this paper the results of an experimental study are presented, which are the lifetime controls of platinum treatment, electron irradiation treatment, and the combined treatment of the above ones. Based on deep level transient spectroscopy (DLTS) measurements, a new level E6 (EC-0.376 eV) is found in the combined lifetime treated (CLT) sample, which is different from the levels of the individual platinum and electron irradiation ones. Comparing the tested VF results of CLT samples with the others, the level E6 is responsible for the degradation of temperature dependence of the forward voltage drop in the FRD. Project supported by the Doctoral Fund of Ministry of Education of China (Grant No. 20111103120016) and the State Grid Corporation of China Program of Science and Technology, China (Grant No. 5455DW140003).

Space radiation effects in InP solar cells

NASA Astrophysics Data System (ADS)

Walters, R. J.; Messenger, S. R.; Summers, G. P.; Burke, E. A.; Keavney, C. J.

1991-12-01

InP solar cells and mesa diodes grown by metalorganic chemical vapor deposition (MOCVD) were irradiated with electrons and protons at room temperature. The radiation-induced defects (RIDs) were characterized by deep level transient spectroscopy (DLTS), and the degradation of the solar cell performance was determined through I-V measurements. The nonionizing energy loss (NIEL) of electrons and protons in InP was calculated as a function of energy from 1 to 200 MeV and compared to the measured defect introduction rates. A linear dependence was evident. InP solar cells showed significantly more radiation resistance than c-Si or GaAs/Ge cells under 1 MeV electron irradiation. Using the calculated InP damage rates and measured damage factors, the performance of InP solar cells as a function of orbital altitude and time in orbit was predicted and compared with the performance of c-Si solar cells in the same environment. In all cases, the InP cells showed highly superior radiation resistance.

Electrical properties of grain boundaries and dislocations in crystalline silicon: Influence of impurity incorporation and hydrogenation

NASA Astrophysics Data System (ADS)

Park, Yongkook

This thesis examines the electrical properties of grain boundaries (GBs) and dislocations in crystalline silicon. The influence of impurity incorporation and hydrogenation on the electrical properties of grain boundaries , as well as the electrical activity of impurity decorated dislocations and the retention of impurities at dislocations at high temperatures have been investigated. The electrical properties of Si GB were examined by C-V, J-V , and capacitance transient methods using aluminum/Si(100)/Si(001) junctions. First, the density of states and the carrier capture cross-sections of the clean GB were evaluated by C-V/J-V analyses. The density of GB states was determined as 4.0x1012 cm-2eV -1. It was found that the states close to the valance band edge have relatively smaller hole capture cross sections than those at higher energy position, and electron capture cross sections are at least two or three orders larger than the corresponding hole capture cross sections. Secondly, the influence of iron contamination and hydrogenation following iron contamination on the electrical properties of (110)/(001) Si GB was characterized by a capacitance transient technique. Compared with the clean sample, iron contamination increased both the density of states by at least three times and the zero-bias barrier height by 70 meV, while reducing by two orders of magnitude the electron/hole capture cross-section ratio. Hydrogenation following iron contamination led to the reduction of the density of Fe-decorated GB states, which was increased to over 2x1013 cm-2eV-1 after iron contamination, to ˜1x1013 cm-2 eV-1 after hydrogenation treatment. The increased zero-bias GB energy barrier due to iron contamination was reversed as well by hydrogen treatment. The density of GB states before and after hydrogenation was evaluated by J-V, C-V and capacitance transient methods using gold/direct-silicon-bonded (DSB) (110) thin silicon top layer/(100) silicon substrate junctions. The GB potential energy barrier in thermal equilibrium was reduced by 70 meV. Whereas the clean sample had a density of GB states of ˜6x1012 cm-2eV-1 in the range of Ev+0.54˜0.64 eV, hydrogenation reduced the density of GB states to ˜9x1011 cm-2eV -1 in the range of Ev+0.56˜0.61 eV, which is about a seven-fold reduction from that of the clean sample. Segregation and thermal dissociation kinetics of hydrogen at a large-angle general GB in crystalline silicon have been investigated using deuterium as a readily identifiable isotope which duplicates hydrogen chemistry. Segregation or trapping of deuterium (hydrogen) introduced was found to take place at (110)/(001) Si GB. The segregation coefficient (k) of deuterium (hydrogen) at GB was determined as k≈24+/-3 at 100°C. Thermal dissociation of deuterium (hydrogen) from GB obeyed first-order kinetics with an activation energy of ˜1.62 eV. The electrical activities of dislocations in a SiGe/Si heterostructure were examined by deep level transient spectroscopy (DLTS) after iron contamination and phosphorous diffusion gettering. DLTS of iron contaminated samples revealed a peak at 210 K, which was assigned to individual iron atoms or very small (<2 nm) precipitates decorated along dislocations. Arrhenius plot of the 210 K peak yielded a hole capture cross section of 2.4x10-14 cm2 and an energy level of 0.42 eV above the valance band. DLTS of the iron contaminated sample revealed that 6x10 14 cm-3 of boron can more effectively trap interstitial iron at room temperature than the strain field/defect sites at 107 ˜108 cm-2 dislocations. Phosphorous diffusion experiments revealed that the gettering efficiency of iron impurities depends on the dislocation density. For regions of high dislocation density, phosphorous diffusion cannot remove all iron impurities decorated at dislocations, suggesting a strong binding of iron impurities at dislocation core defects.

Deep centers in AlGaN-based light emitting diode structures

NASA Astrophysics Data System (ADS)

Polyakov, A. Y.; Smirnov, N. B.; Govorkov, A. V.; Mil'vidskii, M. G.; Usikov, A. S.; Pushnyi, B. V.; Lundin, W. V.

1999-10-01

Deep traps were studied in GaN homojunction and AlGaN/GaN heterojunction light emitting diode (LED) p-i-n structures by means of deep levels transient spectroscopy (DLTS), admittance and electroluminescence (EL) spectra measurements. It is shown that, in homojunction LED structures, the EL spectra comes from recombination involving Mg acceptors in-diffusing into the active i-layer. This Mg in-diffusion is strongly suppressed in heterostructures with the upper p-type layer containing about 5% of Al. As a result the main peak in the EL spectra of heterostructures is shifted toward higher energy compared to homojunctions. Joint doping of the i-layer with Zn and Si allows to shift the main EL peak to longer wavelength. The dominant electron traps observed in the studied LED structures had ionization energies of 0.55 and 0.85 eV. The dominant hole traps had apparent ionization energies of 0.85 and 0.4 eV. The latter traps were shown to be metastable and it is argued that they could be at least in part responsible for the persistent photoconductivity observed in p-GaN.

SNM Movement Detection/Radiation Sensors and Advanced Materials Portfolio Review, CdMnTe (CMT) Gamma Ray Detectors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolotnikov,A.

2009-06-02

The project goals are: (1) Develop CMT radiation detectors - Demonstrate feasibility (Phase 1 is complete) and Improve material properties and device performance; (2) This project will lead to novel radiation detectors - high detection efficiency, high energy-resolution, ambient-temperature operation, and low production cost; and (3) Such detectors are needed in areas of nonproliferation and national security for detection of SNM. Research highlights are: (1) We achieved our Phase-I goal - Demonstration of CMT detector performance approaching that of CZT detectors; (2) Demonstrated that In-doped CMT is much closer to its anticipated performance as radiation detectors than other alternative materials,more » TlBr and HgI{sub 2} - Large crystal volumes, 10{sup 10}{Omega}{center_dot}cm, 3 x 10{sup -3}cm{sup 2}/V, and stable response; and (3) Conducted material and device characterization experiments - Detectors: I-V, {mu}{sub e}, ({mu}{tau}){sub e}, internal E fields, energy spectra, and high-resolution x-ray response mapping data and Materials - DLTS, TCT, PL, EPDs, XRD, PCD and IR transmission.« less

DLTS and in situ C-V analysis of trap parameters in swift 50 MeV Li3+ ion-irradiated Ni/SiO2/Si MOS capacitors

NASA Astrophysics Data System (ADS)

Shashank, N.; Singh, Vikram; Gupta, Sanjeev K.; Madhu, K. V.; Akhtar, J.; Damle, R.

2011-04-01

Ni/SiO2/Si MOS structures were fabricated on n-type Si wafers and were irradiated with 50 MeV Li3+ ions with fluences ranging from 1×1010 to 1×1012 ions/cm2. High frequency C-V characteristics are studied in situ to estimate the build-up of fixed and oxide charges. The nature of the charge build-up with ion fluence is analyzed. Defect levels in bulk Si and its properties such as activation energy, capture cross-section, trap concentration and carrier lifetimes are studied using deep-level transient spectroscopy. Electron traps with energies ranging from 0.069 to 0.523 eV are observed in Li ion-irradiated devices. The dependence of series resistance, substrate doping and accumulation capacitance on Li ion fluence are clearly explained. The study of dielectric properties (tan δ and quality factor) confirms the degradation of the oxide layer to a greater extent due to ion irradiation.

Effect of low-oxygen-concentration layer on iron gettering capability of carbon-cluster ion-implanted Si wafer for CMOS image sensors

NASA Astrophysics Data System (ADS)

Onaka-Masada, Ayumi; Nakai, Toshiro; Okuyama, Ryosuke; Okuda, Hidehiko; Kadono, Takeshi; Hirose, Ryo; Koga, Yoshihiro; Kurita, Kazunari; Sueoka, Koji

2018-02-01

The effect of oxygen (O) concentration on the Fe gettering capability in a carbon-cluster (C3H5) ion-implanted region was investigated by comparing a Czochralski (CZ)-grown silicon substrate and an epitaxial growth layer. A high Fe gettering efficiency in a carbon-cluster ion-implanted epitaxial growth layer, which has a low oxygen region, was observed by deep-level transient spectroscopy (DLTS) and secondary ion mass spectroscopy (SIMS). It was demonstrated that the amount of gettered Fe in the epitaxial growth layer is approximately two times higher than that in the CZ-grown silicon substrate. Furthermore, by measuring the cathodeluminescence, the number of intrinsic point defects induced by carbon-cluster ion implantation was found to differ between the CZ-grown silicon substrate and the epitaxial growth layer. It is suggested that Fe gettering by carbon-cluster ion implantation comes through point defect clusters, and that O in the carbon-cluster ion-implanted region affects the formation of gettering sinks for Fe.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

PubMed

Vogl, Dan T; Martin, Thomas G; Vij, Ravi; Hari, Parameswaran; Mikhael, Joseph R; Siegel, David; Wu, Ka Lung; Delforge, Michel; Gasparetto, Cristina

2017-08-01

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m 2 . Dose-limiting toxicities (DLTs) at 2.4 mg/m 2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK

PubMed Central

Tolcher, Anthony W.; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R.; Patnaik, Amita; Baird, Richard D.; Olmos, David; Garrett, Christopher R.; Skolnik, Jeffrey M.; Rubin, Eric H.; Smith, Paul D.; Huang, Pearl; Learoyd, Maria; Shannon, Keith A.; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P.; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A.; Yan, Li; de Bono, Johann S.

2014-01-01

Purpose KRAS is the most commonly mutated oncogene in human tumours. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumours. Recommended dosing schedules were defined as MK-2206 135 mg weekly and selumetinib 100 mg once-daily. Results Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhoea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical anti-tumour activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion Responses in KRAS-mutant cancers were generally durable. Clinical co-targeting of MEK and AKT signalling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). PMID:25516890

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PubMed

Tolcher, Anthony W; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R; Patnaik, Amita; Baird, Richard D; Olmos, David; Garrett, Christopher R; Skolnik, Jeffrey M; Rubin, Eric H; Smith, Paul D; Huang, Pearl; Learoyd, Maria; Shannon, Keith A; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A; Yan, Li; de Bono, Johann S

2015-02-15

KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). ©2014 American Association for Cancer Research.

The effect of alpha-particle and proton irradiation on the electrical and defect properties of n-GaAs

NASA Astrophysics Data System (ADS)

Goodman, S. A.; Auret, F. D.; Meyer, W. E.

1994-05-01

Radiation damage effects were studied in n-GaAs grown by organo-metallic vapour phase epitaxy (OMVPE) for a wide range of alpha-particle (2.0 MeV and 5.4 MeV) and proton (2.0 MeV) particle fluences, using an americium-241 (Am-241) radio-nuclide and a linear Van de Graaff accelerator as the particle sources. The samples were irradiated at 300 K, after fabricating palladium Schottky barrier diodes (SBDs) on the 1.2 × 10 16 cm 3 Si-doped epitaxial layers. The irradiation-induced defects are characterized using conventional deep level transient spectroscopy (DLTS). A correlation is made between the change in SBD characteristics and the quantity and type of defects introduced during irradiation. It is shown that the two parameters most susceptible to this irradiation are the reverse leakage current of the SBDs and the free carrier density of the epilayer. The introduction rate and the "signatures" of the alpha-particle and proton irradiation-induced defects are calculated and compared to those of similar defects introduced during electron irradiation.

Response of single junction GaAs/GaAs and GaAs/Ge solar cells to multiple doses of 1 MeV electrons

NASA Technical Reports Server (NTRS)

Meier, D. L.; Szedon, J. R.; Bartko, J.; Chung, M. A.

1989-01-01

A comparison of the radiation tolerance of MOCVD-grown GaAs cells and GaAs/Ge cells was undertaken using 1 MeV electrons. The GaAs/Ge cells are somewhat more tolerant of 1 MeV electron irradiation and more responsive to annealing than are the GaAs/GaAs cells examined in this study. However, both types of cells suffer a greater degradation in efficiency than has been observed in other recent studies. The reason for this is not certain, but it may be associated with an emitter thickness which appears to be greater than desired. The deep level transient spectroscopy (DLTS) spectra following irradiation are not significantly different for the GaAs/Ge and the GaAs/GaAs cells, with each having just two peaks. The annealing behavior of these peaks is also similar in the two samples examined. It appears that no penalty in radiation tolerance, and perhaps some benefit, is associated with fabricating MOCVD GaAs cells on Ge substrates rather than GaAs substrates.

p-type doping by platinum diffusion in low phosphorus doped silicon

NASA Astrophysics Data System (ADS)

Ventura, L.; Pichaud, B.; Vervisch, W.; Lanois, F.

2003-07-01

In this work we show that the cooling rate following a platinum diffusion strongly influences the electrical conductivity in weakly phosphorus doped silicon. Diffusions were performed at the temperature of 910 °C in the range of 8 32 hours in 0.6, 30, and 60 Ωrm cm phosphorus doped silicon samples. Spreading resistance profile analyses clearly show an n-type to p-type conversion under the surface when samples are cooled slowly. On the other hand, a compensation of the phosphorus donors can only be observed when samples are quenched. One Pt related acceptor deep level at 0.43 eV from the valence band is assumed to be at the origin of the type conversion mechanism. Its concentration increases by lowering the applied cooling rate. A complex formation with fast species such as interstitial Pt atoms or intrinsic point defects is expected. In 0.6 Ωrm cm phosphorus doped silicon, no acceptor deep level in the lower band gap is detected by DLTS measurement. This removes the opportunity of a pairing between phosphorus and platinum and suggests the possibility of a Fermi level controlled complex formation.

Hydrogen-enhanced clusterization of intrinsic defects and impurities in silicon

NASA Astrophysics Data System (ADS)

Mukashev, B. N.; Abdullin, Kh. A.; Gorelkinskii, Yu. V.; Tamendarov, M. F.; Tokmoldin, S. Zh

2001-01-01

Formation of intrinsic and impurity defect complexes in hydrogenated monocrystalline silicon is studied. Hydrogen was incorporated into samples by different ways: either by proton implantation at 80 and 300 K, or by annealing at 1250°C for 30-60 min in a sealed quartz ampoule containing ∼10 -3 ml of distilled water, or by treatment in hydrogen plasma. Radiation defects were incorporated either during the hydrogen implantation or by additional irradiation with protons or α-particles. The measurements were performed by electron paramagnetic resonance (EPR), deep level transient spectroscopy (DLTS) and infrared absorption (IR) methods. Essential differences of defect formation processes in hydrogenated samples as compared with reference samples were detected. The main reasons responsible for the differences are (i) hydrogen precipitation in a supersaturated solution during thermal treatment; (ii) interaction of hydrogen with defects and impurities and hydrogen-induced formation of defects; (iii) ability of hydrogen to play the role of accelerator of impurities precipitation. These factors result in the formation of vacancy-related, interstitial-related and impurity clusters which are observed only in the presence of hydrogen. The nature of the clusters and possible models of their structure are discussed.

Defect States in InP/InGaAs/InP Heterostructures by Current-Voltage Characteristics and Deep Level Transient Spectroscopy.

PubMed

Vu, Thi Kim Oanh; Lee, Kyoung Su; Lee, Sang Jun; Kim, Eun Kyu

2018-09-01

We studied defect states in In0.53Ga0.47As/InP heterojunctions with interface control by group V atoms during metalorganic chemical vapor (MOCVD) deposition. From deep level transient spectroscopy (DLTS) measurements, two defects with activation energies of 0.28 eV (E1) and 0.15 eV (E2) below the conduction band edge, were observed. The defect density of E1 for In0.53Ga0.47As/InP heterojunctions with an addition of As and P atoms was about 1.5 times higher than that of the heterojunction added P atom only. From the temperature dependence of current- voltage characteristics, the thermal activation energies of In0.53Ga0.47As/InP of heterojunctions were estimated to be 0.27 and 0.25 eV, respectively. It appeared that the reverse light current for In0.53Ga0.47As/InP heterojunction added P atom increased only by illumination of a 940 nm-LED light source. These results imply that only the P addition at the interface can enhance the quality of InGaAs/InP heterojunction.

Investigation of a combined platinum and electron lifetime control treatment for silicon

NASA Astrophysics Data System (ADS)

Jia, Yunpeng; Cui, Zhihang; Yang, Fei; Zhao, Bao; Zou, Shikai; Liang, Yongsheng

2017-02-01

In silicon, the effect of Combined Lifetime Treatment (CLT) involving platinum diffusion and subsequent electron irradiation is different from the separate treatments of platinum diffusion and electron irradiation, even the treatment of electron irradiation followed by platinum diffusion. In this paper, we investigated the experimental behavior of different kinds of lifetime treated samples. We found that the reverse leakage current (Irr) increases with the increasing platinum diffusion temperature or electron irradiation dose in the separate treatments. Conversely, Irr of the CLT samples decreased with rising platinum diffusion temperature at the same dose of subsequent electron irradiation. By deep-level transient spectroscopy (DLTS), a new energy level E7 (Ec -0.376 eV) was found in our CLT samples. The new level E7 suppresses the dominance of the deeper level E8 (Ec -0.476 eV), which is caused by electron irradiation directly and results in Irr's increase. The formation of the level E7 comes from the complex defect-combined effect between platinum atoms and silicon vacancies, and it affects device's characteristics finally. These research will be helpful to the development of platinum-diffused devices used in intense electron irradiation environments.

Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study.

PubMed

Martinelli, Giovanni; Oehler, Vivian G; Papayannidis, Cristina; Courtney, Rachel; Shaik, M Naveed; Zhang, Xiaoxi; O'Connell, Ashleigh; McLachlan, Karen R; Zheng, Xianxian; Radich, Jerald; Baccarani, Michele; Kantarjian, Hagop M; Levin, Wendy J; Cortes, Jorge E; Jamieson, Catriona

2015-08-01

Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. Pfizer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

PubMed

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (<1.25 m²), 100 (1.25 ≤ 1.5 m²), and 120 mg (1.5 m²≥) per day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

Large-area silicon sheet task

NASA Technical Reports Server (NTRS)

Morrison, A. D.

1982-01-01

A set of computer models was used to define a growth system configuration that was then built and used to grow web with lower thermally generated stress. Aspects of research in the edge-defined film-fed growth (EFG) method of making Si ribbon are reported. A technique was developed to determine base resistivity and carrier lifetime in semicrystalline wafers. Automated growth of 150 kg of 15 cm-dia ingot material per crucible is reviewed. Scanning transmisson electron microscopy (STEM) and microprobe investigations of processed EFG ribbon are reported. The chemical composition of the large precipitates was studied. The structural arrangement and the electrical activity of distentions or close to the central twin plane in processed material were studied. The electrical and structural properties of grain boundaries in silicon are discussed. Temperature-dependence measurements of zero-bias conductance, a photoconductivity technique, and deep-level transient spectroscopy (DLTS) were developed. A grooving and staining technique, secondary ion mass spectroscopy, and EBIC measurements in scanning electron microscopy were used to study enhanced diffusion of phosphorus at grain boundaries in polycrystaline silicon. The fundamental mechanisms of abrasion and wear and the deformation of Si by a diamond in various fluid environments are described. The efficiency of solar cells made from EFG ribbon and Semix Inc. material is reported.

Investigation of low leakage current radiation detectors on n-type 4H-SiC epitaxial layers

NASA Astrophysics Data System (ADS)

Nguyen, Khai V.; Chaudhuri, Sandeep K.; Mandal, Krishna C.

2014-09-01

The surface leakage current of high-resolution 4H-SiC epitaxial layer Schottky barrier detectors has been improved significantly after surface passivations of 4H-SiC epitaxial layers. Thin (nanometer range) layers of silicon dioxide (SiO2) and silicon nitride (Si3N4) were deposited on 4H-SiC epitaxial layers using plasma enhanced chemical vapor deposition (PECVD) on 20 μm thick n-type 4H-SiC epitaxial layers followed by the fabrication of large area (~12 mm2) Schottky barrier radiation detectors. The fabricated detectors have been characterized through current-voltage (I-V), capacitance-voltage (C-V), and alpha pulse height spectroscopy measurements; the results were compared with that of detectors fabricated without surface passivations. Improved energy resolution of ~ 0.4% for 5486 keV alpha particles was observed after passivation, and it was found that the performance of these detectors were limited by the presence of macroscopic and microscopic crystal defects affecting the charge transport properties adversely. Capacitance mode deep level transient studies (DLTS) revealed the presence of a titanium impurity related shallow level defects (Ec-0.19 eV), and two deep level defects identified as Z1/2 and Ci1 located at Ec-0.62 and ~ Ec-1.40 eV respectively.

Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002.

PubMed

Caponigro, Francesco

2002-09-01

An international meeting focused on farnesyl transferase inhibitors (FTIs) was held in Naples on 12 April 2002 and represented an excellent occasion to gather most of the clinicians who are involved in clinical trials with this class of new compounds. Oncogene mutations of the gene occur in approximately 30% of all human cancers and may have prognostic significance. Ras protein is normally synthesized as pro-Ras, which undergoes a number of post-translational modifications, among which farnesylation. Processed Ras proteins localize to the inner surface of the plasma membrane, and function as a molecular switch that cycles between an inactive and an active form. When in its active form, either because of the binding of an external ligand or because of its constitutive activation, Ras activates several downstream effectors, such as Raf-1, Rac, Rho and phospahtidylinositol-3 kinase, which mediate important cellular functions, such as proliferation, cytoskeletal organization and others. Interruption of the Ras signaling pathway can be basically achieved in three ways, i.e. inhibition of Ras protein expression through antisense oligonucleotides, prevention of Ras membrane localization and inhibition of Ras downstream effectors. SCH 66336 (lonafarnib; Sarasar), a tricyclic orally active FTI, has been the first of these compounds to undergo clinical development. The toxicity profile observed in all completed phase I/II trials has been fairly similar, since gastrointestinal tract toxicity (nausea, vomiting and diarrhea) and fatigue have generally qualified as dose-limiting toxicity (DLT). One objective response in a patient with pretreated non-small cell lung cancer (NSCLC) was observed. Based on preclinical evidence of synergism between lonafarnib and other anticancer agents, combination studies have been started. In particular, lonafarnib has been combined both with gemcitabine and with paclitaxel in phase I studies. Nausea, vomiting, diarrhea and myelosuppression represented DLTs in these studies, in which an encouraging clinical activity was observed, in particular in pancreatic carcinoma (lonafarnib plus gemcitabine) and in NSCLC (lonafarnib plus paclitaxel). R115777 (Zarnestra) is another novel orally active FT competitive inhibitor in clinical development. Single-agent phase I/II studies have shown that myelotoxicity and neurotoxicity are DLTs, intermittent schedule is probably better tolerated and antitumor activity is observed particularly in breast cancer. A number of combination studies with R115777 have been carried out; taken as a whole, they show that the drug can be easily combined with several anticancer agents and phase III trials exploring the potential benefit from incorporation of R115777 into active chemotherapy regimens are indicated. Two other FTIs are in an earlier stage of clinical development. BMS-214662 has the main advantage of being cytotoxic in nature, rather than cytostatic; in particular, potent antitumor activity in human tumor xenografts of different histologies has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. L-778,123 has been stopped in its clinical development due to its severe and unexpected toxicity, i.e. grade 4 thrombocytopenia and significant Q-T prolongation.

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

PubMed

Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

2018-02-01

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

Phase I Pharmacokinetic Study of the VEGFR Tyrosine Kinase Inhibitor Vatalanib (PTK787) plus Imatinib and Hydroxyurea for Malignant Glioma

PubMed Central

Reardon, David A.; Egorin, Merrill J.; Desjardins, Annick; Vredenburgh, James J.; Beumer, Jan H.; Lagattuta, Theodore F.; Gururangan, Sridharan; Herndon, James E.; Salvado, August J.; Friedman, Henry S.

2009-01-01

Background We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. Methods All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. Results Thirty-seven recurrent patients, including 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. Conclusion Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea are well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and PDGFR, respectively, are safe among recurrent malignant glioma patients and may enhance anti-angiogenesis activity. PMID:19248046

Trade-off between bandwidth and efficiency in semipolar (20 2 ¯ 1 ¯) InGaN/GaN single- and multiple-quantum-well light-emitting diodes

NASA Astrophysics Data System (ADS)

Monavarian, M.; Rashidi, A.; Aragon, A. A.; Nami, M.; Oh, S. H.; DenBaars, S. P.; Feezell, D.

2018-05-01

InGaN/GaN light-emitting diodes (LEDs) with large modulation bandwidths are desirable for visible-light communication. Along with modulation speed, the consideration of the internal quantum efficiency (IQE) under operating conditions is also important. Here, we report the modulation characteristics of semipolar (20 2 ¯ 1 ¯ ) InGaN/GaN (LEDs) with single-quantum well (SQW) and multiple-quantum-well (MQW) active regions grown on free-standing semipolar GaN substrates with peak internal quantum efficiencies (IQEs) of 0.93 and 0.73, respectively. The MQW LEDs exhibit on average about 40-80% higher modulation bandwidth, reaching 1.5 GHz at 13 kA/cm2, but about 27% lower peak IQE than the SQW LEDs. We extract the differential carrier lifetimes (DLTs), RC parasitics, and carrier escape lifetimes and discuss their role in the bandwidth and IQE characteristics. A coulomb-enhanced capture process is shown to rapidly reduce the DLT of the MQW LED at high current densities. Auger recombination is also shown to play little role in increasing the speed of the LEDs. Finally, we investigate the trade-offs between the bandwidth and efficiency and introduce the bandwidth-IQE product as a potential figure of merit for optimizing speed and efficiency in InGaN/GaN LEDs.

4H-SiC p i n diodes grown by sublimation epitaxy in vacuum (SEV) and their application as microwave diodes

NASA Astrophysics Data System (ADS)

Camara, N.; Zekentes, K.; Zelenin, V. V.; Abramov, P. L.; Kirillov, A. V.; Romanov, L. P.; Boltovets, N. S.; Krivutsa, V. A.; Thuaire, A.; Bano, E.; Tsoi, E.; Lebedev, A. A.

2008-02-01

Sublimation epitaxy under vacuum (SEV) was investigated as a method for growing 4H-SiC epitaxial structures for p-i-n diode fabrication. The SEV-grown 4H-SiC material was investigated with scanning electron microscopy (SEM), atomic force microscopy (AFM), x-ray diffraction, photo-luminescence spectroscopy (PL), cathodo-luminescence (CL) spectroscopy, photocurrent method for carrier diffusion length determination, electro-luminescence microscopy (EL), deep level transient spectroscopy (DLTS), C-V profiling and Hall-effect measurements. When possible, the same investigation techniques were used in parallel with similar layers grown by chemical vapour deposition (CVD) epitaxy and the physical properties of the two kind of epitaxied layers were compared. p-i-n diodes were fabricated in parallel on SEV and CVD-grown layers and showed close electrical performances in dc mode in term of capacitance, resistance and transient time switching, despite the lower mobility and the diffusion length of the SEV-grown layers. X-band microwave switches based on the SEV-grown p-i-n diodes have been demonstrated with insertion loss lower than 4 dB and an isolation higher than 17 dB. These single-pole single-throw (SPST) switches were able to handle a pulsed power up to 1800 W in isolation mode, similar to the value obtained with switches incorporating diodes with CVD-grown layers.

Structural and electrical properties of AlN layers grown on silicon by reactive RF magnetron sputtering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazlov, N., E-mail: n.bazlov@spbu.ru; Pilipenko, N., E-mail: nelly.pilipenko@gmail.com; Vyvenko, O.

2016-06-17

AlN films of different thicknesses were deposited on n-Si (100) substrates by reactive radio frequency (rf) magnetron sputtering. Dependences of structure and electrical properties on thickness of deposited films were researched. The structures of the films were analyzed with scanning electron microscopy (SEM) and with transmitting electron microscopy (TEM). Electrical properties of the films were investigated on Au-AlN-(n-Si) structures by means of current-voltage (I-V), capacitance-voltage (C-V) and deep level transient spectroscopy (DLTS) techniques. Electron microscopy investigations had shown that structure and chemical composition of the films were thickness stratified. Near silicon surface layer was amorphous aluminum oxide one contained trapsmore » of positive charges with concentration of about 4 × 10{sup 18} cm{sup −3}. Upper layers were nanocrystalline ones consisted of both wurzite AlN and cubic AlON nanocrystals. They contained traps both positive and negative charges which were situated within 30 nm distance from silicon surface. Surface densities of these traps were about 10{sup 12} cm{sup −2}. Electron traps with activation energies of (0.2 ÷ 0.4) eV and densities of about 10{sup 10} cm{sup −2} were revealed on interface between aluminum oxide layer and silicon substrate. Their densities varied weakly with the film thickness.« less

Persistent photocurrent and deep level traps in PLD-grown In-Ga-Zn-O thin films studied by thermally stimulated current spectroscopy

NASA Astrophysics Data System (ADS)

Wang, Buguo; Anders, Jason; Leedy, Kevin; Schuette, Michael; Look, David

2018-02-01

InGaZnO (IGZO) is a promising semiconductor material for thin-film transistors (TFTs) used in DC and RF switching applications, especially since it can be grown at low temperatures on a wide variety of substrates. Enhancement-mode TFTs based on IGZO thin films grown by pulsed laser deposition (PLD) have been recently fabricated and these transistors show excellent performance; however, compositional variations and defects can adversely affect film quality, especially in regard to electrical properties. In this study, we use thermally stimulated current (TSC) spectroscopy to characterize the electrical properties and the deep traps in PLD-grown IGZO thin films. It was found that the as-grown sample has a DC activation energy of 0.62 eV, and two major traps with activation energies at 0.16-0.26 eV and at 0.90 eV. However, a strong persistent photocurrent (PPC) sometimes exists in the as-grown sample, so we carry out post-growth annealing in an attempt to mitigate the effect. It was found that annealing in argon increases the conduction, produces more PPC and also makes more traps observable. Annealing in air makes the film more resistive, and removes PPC and all traps but one. This work demonstrates that current-based trap emission, such as that associated with the TSC, can effectively reveal electronic defects in highlyresistive semiconductor materials, especially those are not amenable to capacitance-based techniques, such as deeplevel transient spectroscopy (DLTS).

DLTS Analysis and Interface Engineering of Solution Route Fabricated Zirconia Based MIS Devices Using Plasma Treatment

NASA Astrophysics Data System (ADS)

Kumar, Arvind; Mondal, Sandip; Koteswara Rao, K. S. R.

2018-02-01

In this work, we have fabricated low-temperature sol-gel spin-coated and oxygen (O2) plasma treated ZrO2 thin film-based metal-insulator-semiconductor devices. To understand the impact of plasma treatment on the Si/ZrO2 interface, deep level transient spectroscopy measurements were performed. It is reported that the interface state density ( D it) comes down to 7.1 × 1010 eV-1 cm-2 from 4 × 1011 eV-1 cm-2, after plasma treatment. The reduction in D it is around five times and can be attributed to the passivation of oxygen vacancies near the Si/ZrO2 interface, as they try to relocate near the interface. The energy level position ( E T) of interfacial traps is estimated to be 0.36 eV below the conduction band edge. The untreated ZrO2 film displayed poor leakage behavior due to the presence of several traps within the film and at the interface; O2 plasma treated films show improved leakage current density as they have been reduced from 5.4 × 10-8 A/cm2 to 1.98 × 10-9 A/cm2 for gate injection mode and 6.4 × 10-8 A/cm2 to 6.3 × 10-10 A/cm2 for substrate injection mode at 1 V. Hence, we suggest that plasma treatment might be useful in future device fabrication technology.

Performance, Defect Behavior and Carrier Enhancement in Low Energy, Proton Irradiated p(+)nn(+) InP Solar Cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Rybicki, G. C.; Vargas-Aburto, C.; Jain, R. K.; Scheiman, D.

1994-01-01

InP p(+)nn(+) cells, processed by MOCVD, were irradiated by 0.2 MeV protons and their performance and defect behavior observed to a maximum fluence of 10(exp 13)/sq cm. Their radiation induced degradation, over this fluence range, was considerably+less than observed for similarly irradiated, diffused junction n p InP cells. Significant degradation occurred in both the cell's emitter and base regions the least degradation occurring in the depletion region. A significant increase in series resistance occurs at the highest fluenc.e. Two majority carrier defect levels, E7 and E10, are observed by DLTS with activation energies at (E(sub C) - 0.39)eV and (E(sub C) - 0.74)eV respectively. The relative concentration of these defects differs considerably from that observed after 1 MeV electron irradiation. An increased carrier concentration in the cell's n-region was observed at the highest proton fluence, the change in carrier concentration being insignificant at the lower fluences. In agreement with previous results, for 1 and 1.5 MeV electron irradiated InP p(+)n junctions, the defect level E10 is attributed to a complex between zinc, diffused into the n-region from the zinc doped emitter, and a radiation induced defect. The latter is assumed to be either a phosphorus vacancy or interstitial. The increased, or enhanced carrier concentration is attributed to this complex acting as a donor.

Direct identification of Streptococcus agalactiae and capsular type by real-time PCR in vaginal swabs from pregnant women.

PubMed

Morozumi, Miyuki; Chiba, Naoko; Igarashi, Yuko; Mitsuhashi, Naoki; Wajima, Takeaki; Iwata, Satoshi; Ubukata, Kimiko

2015-01-01

Most group B streptococcus (GBS) infections in newborns are with capsular type Ia, Ib, or III. To prevent these infections more effectively, we developed a real-time PCR method to simultaneously detect GBS species and identify these 3 capsular types in vaginal swab samples from women at 36-39 weeks of gestation. DNA to be detected included those of the dltS gene (encoding a histidine kinase specific to GBS) and cps genes encoding capsular types. PCR sensitivity was 10 CFU/well for a 33-35 threshold cycle. Results were obtained within 2 h. Direct PCR results were compared with results obtained from cultures. Samples numbering 1226 underwent PCR between September 2008 and August 2012. GBS positivity rates by direct PCR and after routine culture were 15.7% (n = 192) and 12.6% (n = 154), respectively. Sensitivity and specificity of direct PCR relative to culture were 96.1% and 95.9%. Of GBS positive samples identified by PCR, capsular types determined directly by real-time PCR were Ia (n = 24), Ib (n = 32), and III (n = 26). Real-time PCR using our designed cycling probe is a practical, highly sensitive method for identification of GBS in pregnant carriers, allowing use of prophylactic intrapartum antibiotics in time to cover the possibility of unexpected premature birth. Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

PubMed

Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

2015-05-01

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

Effects of Plasma Hydrogenation on Trapping Properties of Dislocations in Heteroepitaxial InP/GaAs

NASA Technical Reports Server (NTRS)

Ringel, S. A.; Chatterjee, B.

1994-01-01

In previous work, we have demonstrated the effectiveness of a post-growth hydrogen plasma treatment for passivating the electrical activity of dislocations in metalorganic chemical vapor deposition (MOCVD) grown InP on GaAs substrates by a more than two order of magnitude reduction in deep level concentration and an improvement in reverse bias leakage current by a factor of approx. 20. These results make plasma hydrogenation an extremely promising technique for achieving high efficiency large area and light weight heteroepitaxial InP solar cells for space applications. In this work we investigate the carrier trapping process by dislocations in heteroepitaxial InP/GaAs and the role of hydrogen passivation on this process. It is shown that the charge trapping kinetics of dislocations after hydrogen passivation are significantly altered, approaching point defect-like behavior consistent with a transformation from a high concentration of dislocation-related defect bands within the InP bandgap to a low concentration of individual deep levels after hydrogen passivation. It is further shown that the "apparent" activation energies of dislocation related deep levels, before and after passivation, reduce by approx. 70 meV as DLTS fill pulse times are increased from 1 usec. to 1 msec. A model is proposed which explains these effects based on a reduction of Coulombic interaction between individual core sites along the dislocation cores by hydrogen incorporation. Knowledge of the trapping properties in these specific structures is important to develop optimum, low loss heteroepitaxial InP cells.

A comparison of point defects in Cd1-xZnxTe1-ySey crystals grown by Bridgman and traveling heater methods

NASA Astrophysics Data System (ADS)

Gul, R.; Roy, U. N.; Camarda, G. S.; Hossain, A.; Yang, G.; Vanier, P.; Lordi, V.; Varley, J.; James, R. B.

2017-03-01

In this paper, the properties of point defects in Cd1-xZnxTe1-ySey (CZTS) radiation detectors are characterized using deep-level transient spectroscopy and compared between materials grown using two different methods, the Bridgman method and the traveling heater method. The nature of the traps was analyzed in terms of their capture cross-sections and trap concentrations, as well as their effects on the measured charge-carrier trapping and de-trapping times, and then compared for the two growth techniques. The results revealed that Se addition to CdZnTe can reduce the VCd- concentration. In Travelling Heater Method (THM) and Bridgman Method (BM) grown CZTS detectors, besides a few similarities in the shallow and medium energy traps, there were major differences in the deep traps. It was observed that the excess-Te and lower growth-temperature conditions in THM-grown CZTS led to a complete compensation of VCd- and two additional traps (attributed to Tei- and TeCd++ appearing at around Ev + 0.26 eV and Ec - 0.78 eV, respectively). The 1.1-eV deep trap related to large Te secondary phases was a dominant trap in the BM-grown CZTS crystals. In addition to i-DLTS data, the effects of point defects induced due to different processing techniques on the detector's resistivity, spectral response to gammas, and μτ product were determined.

A Comparison of Point Defects in Cd 1-xZn xTe 1-ySe y Crystals Grown by Bridgman and Traveling Heater Methods

DOE PAGES

Gul, R.; Roy, U. N.; Camarda, G. S.; ...

2017-03-28

In this study, the properties of point defects in Cd 1–xZn xTe 1–ySe y (CZTS) radiation detectors are characterized using deep-level transient spectroscopy and compared between materials grown using two different methods, the Bridgman method and the traveling heater method. The nature of the traps was analyzed in terms of their capture cross-sections and trap concentrations, as well as their effects on the measured charge-carrier trapping and de-trapping times, and then compared for the two growth techniques. The results revealed that Se addition to CdZnTe can reduce the V Cd – concentration. In Travelling Heater Method (THM) and Bridgman Methodmore » (BM) grown CZTS detectors, besides a few similarities in the shallow and medium energy traps, there were major differences in the deep traps. It was observed that the excess-Te and lower growth-temperature conditions in THM-grown CZTS led to a complete compensation of V Cd – and two additional traps (attributed to Te i – and Te Cd ++ appearing at around E v + 0.26 eV and E c – 0.78 eV, respectively). The 1.1-eV deep trap related to large Te secondary phases was a dominant trap in the BM-grown CZTS crystals. In addition to i-DLTS data, the effects of point defects induced due to different processing techniques on the detector's resistivity, spectral response to gammas, and μτ product were determined.« less

Carbon-hydrogen-related complexes in Si

NASA Astrophysics Data System (ADS)

Kolkovsky, Vl.; Stübner, R.; Gwozdz, K.; Weber, J.

2018-04-01

Several deep level transient spectroscopy (DLTS) peaks (E42, E65, E75, E90, E262, and H180) are observed in n- and p-type Czochralski-grown Si samples subjected to hydrogenation by a dc H plasma treatment. The concentration of the defects is found to be proportional to the carbon and hydrogen content in our samples. The analysis of the depth profiles performed in Si samples hydrogenated by wet chemically etching shows that all these defects contain a single H atom. E65 and E75 appear only in samples with a high oxygen content which shows that oxygen is a constituent of these defects. The analysis of the enhancement of the emission rate of the defects with electric field shows that E65, E75, E90, and E262 are single acceptors whereas E42 is a double acceptor. The presence of a barrier for hole capture (about 53 meV) can explain the absence of the enhancement of the emission rate of H180, which can be attributed to a single acceptor state. From a comparison with theory, we assign E90 to CH1BC, E42 (E262) to CH1AB, and H180 to CH1Td. The similarity of the electrical properties of E65 and E75 to those of E90 suggest that E65 and E75 may originate from the CH1BC defect with an oxygen atom in its nearest neighborhood. Our results on the CH-related complexes give a conclusive explanation of some previously reported controversial experimental data.

Radiation effects on p+n InP junctions grown by MOCVD

NASA Technical Reports Server (NTRS)

Messenger, Scott R.; Walters, Robert J.; Panunto, M. J.; Summers, Geoffrey P.

1994-01-01

The superior radiation resistance of InP over other solar cell materials such as Si or GaAs has prompted the development of InP cells for space applications. The early research on radiation effects in InP was performed by Yamaguchi and co-workers who showed that, in diffused p-InP junctions, radiation-induced defects were readily annealed both thermally and by injection, which was accompanied by significant cell recovery. More recent research efforts have been made using p-InP grown by metalorganic chemical vapor deposition (MOCVD). While similar deep level transient spectroscopy (DLTS) results were found for radiation induced defects in these cells and in diffused junctions, significant differences existed in the annealing characteristics. After injection annealing at room temperature, Yamaguchi noticed an almost complete recovery of the photovoltaic parameters, while the MOCVD samples showed only minimal annealing. In searching for an explanation of the different annealing behavior of diffused junctions and those grown by MOCVD, several possibilities have been considered. One possibility is the difference in the emitter structure. The diffused junctions have S-doped graded emitters with widths of approximately 0.3 micrometers, while the MOCVD emitters are often doped with Si and have widths of approximately 300A (0.03 micrometers). The difference in the emitter thickness can have important effects, e.g. a larger fraction of the total photocurrent is generated in the n-type material for thicker emitters. Therefore the properties of the n-InP material may explain the difference in the observed overall annealing behavior of the cells.

Tolerability and pharmacokinetic profile of a sunitinib powder formulation in pediatric patients with refractory solid tumors: a Children's Oncology Group study.

PubMed

DuBois, Steven G; Shusterman, Suzanne; Reid, Joel M; Ingle, Ashish M; Ahern, Charlotte H; Baruchel, Sylvain; Glade-Bender, Julia; Ivy, Percy; Adamson, Peter C; Blaney, Susan M

2012-04-01

Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m(2)/day. This study was conducted to evaluate sunitinib given as a powder formulation. Sunitinib 15 mg/m(2) was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated. 12 patients, median age 13 (range 4-21) years, were treated. The most common first-cycle toxicities were leucopenia (n = 6), fatigue (n = 5), neutropenia (n = 4), and hypertension (n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand-foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6-36) ng/ml was reached at a median of 4 (range 4-8) h after the first dose. The median exposure (AUC(0-48)) was 585 (range 196-1,059) h ng/l. The median half-life was 23 (range 13-36) h. The median trough concentration measured before day 14 dosing was 32 (range 12-58) ng/ml. The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib.

Defect-related degradation of III-V/Silicon 1.55 μm DBR laser diodes

NASA Astrophysics Data System (ADS)

Buffolo, Matteo; Meneghini, Matteo; De Santi, Carlo; Trivellin, Nicola; Davenport, Michael L.; Bowers, John E.; Meneghesso, Gaudenzio; Zanoni, Enrico

2018-02-01

This paper reports on an extensive investigation on the degradation mechanisms that may limit the long term reliability of heterogeneous III-V/Silicon DBR laser diodes for integrated telecommunication applications in the 1.55 μm window. The devices under test, aged for up to 500 hours under different bias conditions, showed a gradual variation of both optical (L-I) and electrical (I-V, C-V) characteristics. In particular, the laser diodes exhibited an increase in the threshold current, a decrease of the turn-on voltage and an increase in the apparent charge density within the space-charge region, which was extrapolated from C-V measurements. For longer stress times, these two latter processes were found to be well correlated with the worsening of the optical parameters, which suggests that degradation occurred due to an increase in the density of defects within the active region, with consequent decrease in the non-radiative (SRH) lifetime. This conclusion is also supported by the fact that during stress the apparent charge profiles indicated a re-distribution of charge within the junction. A preliminary investigation on the physical origin of the defects responsible for degradation was carried out by DLTS measurements, which revealed the presence of five different deep levels, with a main trap located around 0.43 eV above the valence band energy. This trap was found to be compatible with an interface defect located between the In0.53AlxGa0.47-xAs SCH region and the InP layer.

A Comparison of Point Defects in Cd 1-xZn xTe 1-ySe y Crystals Grown by Bridgman and Traveling Heater Methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gul, R.; Roy, U. N.; Camarda, G. S.

In this study, the properties of point defects in Cd 1–xZn xTe 1–ySe y (CZTS) radiation detectors are characterized using deep-level transient spectroscopy and compared between materials grown using two different methods, the Bridgman method and the traveling heater method. The nature of the traps was analyzed in terms of their capture cross-sections and trap concentrations, as well as their effects on the measured charge-carrier trapping and de-trapping times, and then compared for the two growth techniques. The results revealed that Se addition to CdZnTe can reduce the V Cd – concentration. In Travelling Heater Method (THM) and Bridgman Methodmore » (BM) grown CZTS detectors, besides a few similarities in the shallow and medium energy traps, there were major differences in the deep traps. It was observed that the excess-Te and lower growth-temperature conditions in THM-grown CZTS led to a complete compensation of V Cd – and two additional traps (attributed to Te i – and Te Cd ++ appearing at around E v + 0.26 eV and E c – 0.78 eV, respectively). The 1.1-eV deep trap related to large Te secondary phases was a dominant trap in the BM-grown CZTS crystals. In addition to i-DLTS data, the effects of point defects induced due to different processing techniques on the detector's resistivity, spectral response to gammas, and μτ product were determined.« less

Effects of plasma hydrogenation on trapping properties of dislocations in heteroepitaxial InP/GaAs

NASA Technical Reports Server (NTRS)

Ringel, S. A.; Chatterjee, B.

1994-01-01

In previous work, we have demonstrated the effectiveness of a post-growth hydrogen plasma treatment for passivating the electrical activity of dislocations in metalorganic chemical vapor deposition (MOCVD) grown InP on GaAs substrates by a more than two order of magnitude reduction in deep level concentration and an improvement in reverse bias leakage current by a factor of approximately 20. These results make plasma hydrogenation an extremely promising technique for achieving high efficiency large area and light weight heteroepitaxial InP solar cells for space applications. In this work we investigate the carrier trapping process by dislocations in heteroepitaxial InP/GaAs and the role of hydrogen passivation on this process. It is shown that the charge trapping kinetics of dislocations after hydrogen passivation are significantly altered, approaching point defect-like behavior consistent with a transformation from a high concentration of dislocation-related defect bands within the InP bandgap to a low concentration of individual dislocation related deep levels, before and after passivation. It is further shown that the 'apparent' activation energies of dislocation related deep levels, before and after passivation, reduce by approximately 70 meV as DLTS fill pulse times are increased from 1 microsecond to 1 millisecond. A model is proposed which explains these effects based on a reduction of Coulombic interaction between individual core sites along the dislocation cores by hydrogen incorporation. Knowledge of the trapping properties in these specific structures is important to develop optimum, low loss heteroepitaxial InP cells.

Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors.

PubMed

Gandhi, Leena; Bahleda, Rastislav; Tolaney, Sara M; Kwak, Eunice L; Cleary, James M; Pandya, Shuchi S; Hollebecque, Antoine; Abbas, Richat; Ananthakrishnan, Revathi; Berkenblit, Anna; Krygowski, Mizue; Liang, Yali; Turnbull, Kathleen W; Shapiro, Geoffrey I; Soria, Jean-Charles

2014-01-10

Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.

PubMed

Hong, David S; Kurzrock, Razelle; Supko, Jeffrey G; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J; Ferguson, Deborah A; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I; Dezube, Bruce J

2012-06-15

Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2-related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. ©2012 AACR.

A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

PubMed Central

Hong, David S.; Kurzrock, Razelle; Supko, Jeffrey G.; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J.; Ferguson, Deborah A.; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I.; Dezube, Bruce J.

2015-01-01

Purpose Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. PMID:22634319

A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03).

PubMed

Cooper, Todd M; Sison, Edward Allan Racela; Baker, Sharyn D; Li, Lie; Ahmed, Amina; Trippett, Tanya; Gore, Lia; Macy, Margaret E; Narendran, Aru; August, Keith; Absalon, Michael J; Boklan, Jessica; Pollard, Jessica; Magoon, Daniel; Brown, Patrick A

2017-08-01

Plerixafor, a reversible CXCR4 antagonist, inhibits interactions between leukemic blasts and the bone marrow stromal microenvironment and may enhance chemosensitivity. A phase 1 trial of plerixafor in combination with intensive chemotherapy in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) was performed to determine a tolerable and biologically active dose. Plerixafor was administered daily for 5 days at four dose levels (6, 9, 12, and 15 mg/m 2 /dose) followed 4 hr later by high-dose cytarabine (every 12 hr) and etoposide (daily). Nineteen patients (13 with AML, 5 with ALL, 1 with MDS) were treated. The most common grade 3 or greater nonhematologic toxicities attributable to plerixafor were febrile neutropenia and hypokalemia. There were no dose-limiting toxicities (DLTs). Plerixafor exposure increased with increasing dose levels and clearance was similar on days 1 and 5. Eighteen patients were evaluable for response. Two patients achieved complete remission (CR) and one patient achieved CR with incomplete hematologic recovery (CRi): all three had AML. No responses were seen in patients with ALL or MDS. Plerixafor mobilized leukemic blasts into the peripheral blood in 14 of 16 evaluable patients (median 3.4-fold increase), and the degree of mobilization correlated with surface CXCR4 expression. Plerixafor, in combination with high-dose cytarabine and etoposide, was well tolerated in children and young adults with relapsed/refractory acute leukemias and MDS. While biologic responses were observed, clinical responses in this heavily pretreated cohort were modest. © 2017 Wiley Periodicals, Inc.

Characterization and modeling of low energy ion-induced damage in III-V semiconductors

NASA Astrophysics Data System (ADS)

Chen, Ching-Hui

1997-11-01

Low energy ion-induced damage (sub-keV) created during dry etching processes can extend quite deeply into materials. A systematic study on the deep penetration of dry etch-induced damage is necessary to improve device performance and helpful in further understanding the nature of defect propagation in semiconductors. In this study, a phenomenological model of dry etching damage that includes both effects of ion channeling and defect diffusion has been developed. It underscores that in addition to ion channeling, enhanced defect diffusion also plays an important role in establishing the damage profile. Further, the enhanced diffusion of dry etch- induced damage was experimentally observed for the first time by investigating the influences of concurrent above- bandgap laser illumination and low energy Ar+ ion bombardment on the damage profiles of GaAs/AlGaAs and InP-GaAs/InP heterostructures. The results indicate that non-radiative recombination of electron and hole pairs at defect sites is responsible for the observed radiation enhanced diffusion. DLTS measurements are also employed to characterize the nature of the enhanced diffusion in n-GaAs and reveal that a major component of the ion- induced defects is associated with primary point defects. Using the better understanding of the damage propagation in dry etched materials, a thin layer of low temperature grown GaAs (~200A) was utilized to stop defect propagation during dry etching process. This approach has been successfully applied to reduce ion damage that would occur during the formation of a dry-etch gate recess of a high electron mobility transistor. Finally, some future experiments are proposed and conceptually described, which would further clarify some of the many outstanding issues in the understanding and mitigation of etch- induced damage.

A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Ludmila Katherine; Grecula, John; Jia, Guang

2012-11-15

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m{sup 2}, 48 mg/m{sup 2}, 72 mg/m{sup 2}) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed duringmore » RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m{sup 2} 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.« less

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PubMed

Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

2016-01-01

The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. NCT01149343, Results.

A Phase I and pharmacodynamic study of AT9283, a small molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis

PubMed Central

Foran, James; Ravandi, Farhad; Wierda, William; Garcia-Manero, Guillermo; Verstovsek, Srdan; Kadia, Tapan; Burger, Jan; Yule, Murray; Langford, Gillian; Lyons, John; Ayrton, John; Lock, Victoria; Borthakur, Gautham; Cortes, Jorge; Kantarjian, Hagop

2014-01-01

Purpose To identify the MTD of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics and preliminary evidence of efficacy. Patients and Methods AT9283 was administered as a continuous 72h infusion every 21 days. Doses were escalated by a standard 3+3 design. After the MTD for the 72h infusion was identified, infusion duration was increased incrementally to 96h and 120h. In total, 48 patients received ≥1 cycle of AT9283. Median age was 61 years (range 22–86 years), with 56% men, 75% diagnosed with AML, and 89% having received ≥3 (up to 16) prior lines of therapy. Results 324 mg/m2/72h AT9283 was determined to be the MTD. DLTs were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leucopenia and mucositis. Bone marrow blasts decreased ≥38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of aurora kinase B inhibition. Two patients with accelerated phase CML showed evidence of benefit, manifest as a cytogenetic response in one case; one patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. Conclusion AT9283 tolerability was strongly dose dependent with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations. PMID:24355079

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hickey, Ryan; Mulcahy, Mary F.; Lewandowski, Robert J.

Purpose: Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ({sup 90}Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of {sup 90}Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Methods and Materials: Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the secondmore » cycle, whole-liver {sup 90}Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after {sup 90}Y infusion. If a DLT was not observed, the {sup 90}Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of {sup 90}Y with full-dose capecitabine. Results: Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing {sup 90}Y MTD were not met, indicating an MTD of >170 Gy. Conclusion: The MTD of {sup 90}Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest {sup 90}Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.« less

Partially Ionized Beam Deposition of Silicon-Dioxide and Aluminum Thin Films - Defects Generation.

NASA Astrophysics Data System (ADS)

Wong, Justin Wai-Chow

1987-09-01

Detect formation in SiO_2 and Al thin films and interfaces were studied using a partially ionized beam (PIB) deposition technique. The evaporated species (the deposition material) were partially ionized to give an ion/atom ratio of <=q0.1% and the substrate was biased at 0-5kV during the deposition. The results suggest that due to the ion bombardment, stoichiometric SiO_2 films can be deposited at a low substrate temperature (~300 ^circC) and low oxygen pressure (<=q10^{-4} Torr). Such deposition cannot be achieved using conventional evaporation-deposition techniques. However, traps and mobile ions were observed in the oxide and local melt-down was observed when a sufficiently high electric field was applied to the film. For the PIB Al deposition on the Si substrate, stable Al/Si Schottky contact was formed when the substrate bias was <=q1kV. For a substrate bias of 2.5kV, the capacitance of the Al/Si interface increased dramatically. A model of self-ion implantation with a p-n junction created by the Al^+ ion implantation was proposed and tested to explain the increase of the interface capacitance. Several deep level states at the Al/Si interface were observed using Deep Level Transient Spectroscopy (DLTS) technique when the film was deposited at a bias of 3kV. The PIB Al films deposited on the Si substrate showed unusually strong electromigration resistance under high current density operation. This phenomenon was explained by the highly oriented microstructure of the Al films created by the self-ion bombardment during deposition. These findings show that PIB has potential applications in a number of areas, including low temperature thin film deposition, and epitaxial growth of thin films in the microelectronics thin film industry.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

PubMed Central

Rini, Brian I.; Garcia, Jorge A.; Cooney, Matthew M.; Elson, Paul; Tyler, Allison; Beatty, Kristi; Bokar, Joseph; Mekhail, Tarek; Bukowski, R.M.; Budd, G. Thomas; Triozzi, Pierre; Borden, Ernest; Ivy, Percy; Chen, Helen X.; Dolwati, Afshin; Dreicer, Robert

2009-01-01

Purpose Bevacizumab is an antibody against vascular endothelial growth factor (VEGF); sunitinib is an inhibitor of VEGF and related receptors. The safety and maximum tolerated dose (MTD) of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level 5 mg/kg) on days 1, 15 and 29 of a 42-day cycle. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. Results Thirty-eight patients were enrolled. Pts received a median of 3 cycles of treatment (range, 1–17+). There was one DLT (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed RECIST-defined PR (18%; 95% confidence interval: 8–34%). Nineteen of the 32 patients with a post-baseline scan (59%) had at least some reduction in overall tumor burden (median 32%, range 3–73%). Conclusions The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Anti-tumor activity was observed across multiple solid tumors. PMID:19773375

A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission.

PubMed

O'Cearbhaill, Roisin E; Ragupathi, Govind; Zhu, Jianglong; Wan, Qian; Mironov, Svetlana; Yang, Guangbin; Spassova, Maria K; Iasonos, Alexia; Kravetz, Sara; Ouerfelli, Ouathek; Spriggs, David R; Danishefsky, Samuel J; Sabbatini, Paul J

2016-04-22

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011-Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient's pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36-68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2-39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer

PubMed Central

Cutsem, Eric Van; Eng, Cathy; Nowara, Elzbieta; Świeboda-Sadlej, Anna; Tebbutt, Niall C.; Mitchell, Edith; Davidenko, Irina; Stephenson, Joe; Elez, Elena; Prenen, Hans; Deng, Hongjie; Tang, Rui; McCaffery, Ian; Oliner, Kelly S.; Chen, Lisa; Gansert, Jennifer; Loh, Elwyn; Smethurst, Dominic; Tabernero, Josep

2015-01-01

Purpose Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8,10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. PMID:24919569

High and low energy proton radiation damage in p/n InP MOCVD solar cells

NASA Technical Reports Server (NTRS)

Rybicki, George; Weinberg, Irving; Scheiman, Dave; Vargas-Aburto, Carlos

1995-01-01

InP p(+)nn(+) MOCVD solar cells were irradiated with 0.2 MeV and 10 MeV protons to a fluence of 10(exp 13)/sq cm. The degradation of power output, IV behavior, carrier concentration and defect concentration were observed at intermediate points throughout the irradiations. The 0.2 MeV proton irradiated solar cells suffered much greater and more rapid degradation in power output than those irradiated with 10 meV protons. The efficiency losses were accompanied by larger increases in the recombination currents in the 0.2 MeV proton irradiated solar cells. The low energy proton irradiations also had a larger impact on the series resistance of the solar cells. Despite the radiation induced damage, the carrier concentration in the base of the solar cells showed no reduction after 10 MeV or 0.2 MeV proton irradiations and even increased during irradiation with 0.2 MeV protons. In a DLTS study of the irradiated samples, the minority carrier defects H4 and H5 at E(v) + 0.33 and E(v) + 0.52 eV and the majority carrier defects E7 and E10 at E(c)- 0.39 and E(c)-0.74 eV, were observed. The defect introduction rates for the 0.2 MeV proton irradiations were about 20 times higher than for the 10 MeV proton irradiations. The defect E10, observed here after irradiation, has been shown to act as a donor in irradiated n-type InP and may be responsible for obscuring carrier removal. The results of this study are consistent with the much greater damage produced by low energy protons whose limited range causes them to stop in the active region of the solar cell.

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma

PubMed Central

Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Sathornsumetee, Sith; Rich, Jeremy N.; Quinn, Jennifer A.; Lagattuta, Theodore F.; Egorin, Merrill J.; Gururangan, Sridharan; McLendon, Roger; Herndon, James E.; Friedman, Allan H.; Salvado, August J.; Friedman, Henry S.

2008-01-01

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150–200 mg/m2 per day on days 4–8 plus imatinib mesylate administered orally on days 1–8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n = 28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population. PMID:18359865

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

PubMed

Trucco, Matteo; Barredo, Julio C; Goldberg, John; Leclerc, Gilles M; Hale, Gregory A; Gill, Jonathan; Setty, Bhuvana; Smith, Tiffany; Lush, Richard; Lee, Jae K; Reed, Damon R

2018-06-01

Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m 2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m 2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels. © 2018 Wiley Periodicals, Inc.

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer.

PubMed

Satoh, Taroh; Yamada, Yasuhide; Muro, Kei; Hayashi, Hidetoshi; Shimada, Yasuhiro; Takahari, Daisuke; Taku, Keisei; Nakajima, Takako Eguchi; Shi, Xiaojin; Brown, Kathryn H; Boku, Narikazu

2012-02-01

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer. Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m(2) iv day 1) plus S-1 (40-60 mg bid, days 1-21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m(2) iv, day 1) plus capecitabine (1,000 mg/m(2) bid, days 1-14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1. Fourteen patients (Arm A, n = 6; Arm B, n = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n = 1; Arm B, n = 2) partial responses that were ongoing at data cut-off. Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.

Tolerability and pharmacokinetic profile of a sunitinib powder formulation in pediatric patients with refractory solid tumors: a Children’s Oncology Group study

PubMed Central

Shusterman, Suzanne; Reid, Joel M.; Ingle, Ashish M.; Ahern, Charlotte H.; Baruchel, Sylvain; Glade-Bender, Julia; Ivy, Percy; Adamson, Peter C.; Blaney, Susan M.

2012-01-01

Purpose Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m2/day. This study was conducted to evaluate sunitinib given as a powder formulation. Methods Sunitinib 15 mg/m2 was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated. Results 12 patients, median age 13 (range 4–21) years, were treated. The most common first-cycle toxicities were leucopenia (n = 6), fatigue (n = 5), neutropenia (n = 4), and hypertension (n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand–foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6–36) ng/ml was reached at a median of 4 (range 4–8) h after the first dose. The median exposure (AUC0–48) was 585 (range 196–1,059) h ng/l. The median half-life was 23 (range 13–36) h. The median trough concentration measured before day 14 dosing was 32 (range 12–58) ng/ml. Conclusions The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib. PMID:22179104

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PubMed

Fakih, Marwan G; Fetterly, Gerald; Egorin, Merrill J; Muindi, Josephia R; Espinoza-Delgado, Igor; Zwiebel, James A; Litwin, Alan; Holleran, Julianne L; Wang, Kangsheng; Diasio, Robert B

2010-07-15

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. Copyrighth 2010 AACR.

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors

PubMed Central

Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

2010-01-01

Purpose We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily × 3 or 600 mg orally twice daily × 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. PMID:20463088

A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study.

PubMed

Sato, Yasushi; Hirakawa, Masahiro; Ohnuma, Hiroyuki; Takahashi, Minoru; Okamoto, Tetsuro; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Furuhata, Tomohisa; Takemasa, Ichiro; Kato, Junji; Takayama, Tetsuji

2017-12-01

The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100 mg/m 2 , day 1), capecitabine (1700 mg/m 2 per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m 2 for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m 2 , day 1 and, thereafter, 250 mg/m 2 every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m 2 . Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m 2 . The observed response rate was promising and warrants further investigation.

Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma.

PubMed

Mody, Rajen; Zhao, Lili; Yanik, Gregory Anthony; Opipari, Valerie

2017-11-01

Prognosis for relapsed/refractory high-risk neuroblastoma (HR-NBL) remains poor. Bortezomib, a proteasome inhibitor, has shown preclinical activity against NBL as a single agent and in combination with cytotoxic chemotherapy including irinotecan. Eighteen HR-NBL patients with primary refractory (n = 8) or relapsed (n = 10) disease were enrolled in a Phase I study using modified Time To Event Continual Reassessment Method. Bortezomib (1.2 mg/m 2 /day) was administered on days 1, 4, 8, and 11 intravenously (IV) and irinotecan was given IV on days 1-5 (35, 40, or 45 mg/m 2 /day, on dose levels [DL] 1-3, respectively). The maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and response rate were examined. Eighteen NBL patients were evaluable for toxicity; 17 were evaluable for response assessment. A total of 142 courses were delivered (mean 8.2, median 2, range 1-48), with two patients receiving more than 40 courses of therapy. Two DLTs were reported, including a grade 4 thrombocytopenia (DL2) and a grade 3 irritability (DL3). MTD was estimated as DL3. Two of 17 (12%) evaluable patients showed objective responses (ORs) lasting more than 40 courses, including 1 partial remission and 1 complete remission. Four patients (23%) had prolonged stable disease (SD) lasting six or more courses, with a total of 35% study patients demonstrating clinical benefit in the form of prolonged OR or SD. The combination of bortezomib and irinotecan was well tolerated by patients with relapsed/refractory NBL with favorable toxicity profile. It also showed modest but promising clinical activity and merits further testing in Phase II studies. © 2017 Wiley Periodicals, Inc.

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

PubMed Central

Rampurwala, Murtuza; Wisinski, Kari B; Burkard, Mark E; Ehsani, Sima; O’Regan, Ruth M; Carmichael, Lakeesha; Kim, KyungMann; Kolesar, Jill; Tevaarwerk, Amye J

2017-01-01

Intro Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3+3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n=4) and bone pain (n=3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n=2). The only grade 3 AE was hypertension (n=2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer. PMID:27826831

TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study

PubMed Central

Bang, Yung-Jue; Takano, Toshimi; Lin, Chia-Chi; Fasanmade, Adedigbo; Yang, Huyuan; Danaee, Hadi; Asato, Takayuki; Kalebic, Thea; Wang, Hui; Doi, Toshihiko

2018-01-01

Purpose This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). Materials and Methods Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. Results Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. Conclusion TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose. PMID:28494535

Phase I Trial of Aflibercept (VEGF Trap) with Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients with High-Grade Gliomas

PubMed Central

Nayak, Lakshmi; de Groot, John; Wefel, Jeffrey S; Cloughesy, Timothy F; Lieberman, Frank; Chang, Susan M; Omuro, Antonio; Drappatz, Jan; Batchelor, Tracy T; DeAngelis, Lisa M; Gilbert, Mark R; Aldape, Kenneth D; Yung, Alfred WK; Fisher, Joy; Ye, Xiaobu; Chen, Alice; Grossman, Stuart; Prados, Michael; Wen, Patrick Y

2017-01-01

Background Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor (PlGF), depleting circulating levels of these growth factors. Methods The Adult Brain Tumor Consortium (ABTC) conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG) with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Results Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4mg/kg every 2 weeks. Dose limiting toxicities (DLTs) at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. Conclusions This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4mg/kg every 2 weeks. PMID:28116649

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fury, Matthew G.; Department of Medicine, Weill Cornell Medical College, New York, New York; Lee, Nancy Y.

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neckmore » cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.« less

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients.

PubMed

Zweifel, Martin; Thürlimann, Beat; Riniker, Salome; Weder, Patrik; von Moos, Roger; Pagani, Olivia; Bigler, Martin; Rothgiesser, Karin M; Pilop, Christiane; Hawle, Hanne; Brauchli, Peter; Tapia, Coya; Schoenfeld, Wolfgang; Sessa, Cristiana

2017-10-01

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. © 2017 The authors.

Incorporating lower grade toxicity information into dose finding designs

PubMed Central

Iasonos, Alexia; Zohar, Sarah; O’Quigley, John

2012-01-01

Background Toxicity grades underlie the definition of a dose limiting toxicity (DLT) but in the majority of phase I designs, the information contained in the individual grades is not used. Some authors have argued that it may be more appropriate to consider a polytomous rather than dichotomous response. Purpose We investigate whether the added information on individual grades can improve the operating characteristics of the Continual Reassessment Method (CRM). Methods We compare the original CRM design for a binary response with two stage CRM designs which make di erent use of lower-grade toxicity information via simulations. Specifically we study; a two-stage design that utilizes lower-grade toxicities in the first stage only, during the initial non model-based escalation, and two-stage designs where lower grades are used throughout the trial via explicit models. We postulate a model relating the rates of lower grade toxicities to the rate of DLTs, or assume the relative rates of low to high grade toxicities is unknown. The designs were compared in terms of accuracy, patient allocation and precision. Results Significant gains can be achieved when using grades in the first stage of a two-stage design. Otherwise, only modest improvements are seen when the information on grades is exploited via the use of explicit models, where the parameters are known precisely. CRM with some use of grade information, increases the number of patients treated at the MTD by approximately 5%. The additional information from lower grades can lead to a small increase in the precision of our estimate of the MTD. Limitations Our comparisons are not exhaustive and it would be worth studying other models and situations. Conclusions Although, the gains in performance were not as great as we had hoped, we observed no cases where the performance of CRM was poorer. Our recommendation is that investigators might consider using graded toxicities at the design stage. PMID:21835856

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

PubMed

Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

2017-03-01

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

PubMed

Diamond, Jennifer R; Goff, Barbara; Forster, Martin D; Bendell, Johanna C; Britten, Carolyn D; Gordon, Michael S; Gabra, Hani; Waterhouse, David M; Poole, Mark; Ross Camidge, D; Hamilton, Erika; Moore, Kathleen M

2017-10-01

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m 2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

High and Low Energy Proton Radiation Damage in p/n InP MOCVD Solar Cells

NASA Technical Reports Server (NTRS)

Rybicki, George; Weinberg, Irv; Scheiman, Dave; Vargas-Aburto, Carlos; Uribe, Roberto

1995-01-01

InP p(+)/n/n(+) solar cells, fabricated by metal organic chemical vapor deposition, (MOCVD) were irradiated with 0.2 MeV and 10 MeV protons to a fluence of 10(exp 13)/sq cm. The power output degradation, IV behavior, carrier concentration and defect concentration were observed at intermediate points throughout the irradiations. The 0.2 MeV proton-irradiated solar cells suffered much greater and more rapid degradation in power output than those irradiated with 10 MeV protons. The efficiency losses were accompanied by larger increases in the recombination currents in the 0.2 MeV proton-irradiated solar cells. The low energy proton irradiations also had a larger impact on the series resistance of the solar cells. Despite the radiation induced damage, the carrier concentration in the base of the solar cells showed no reduction after 10 MeV or 0.2 MeV proton irradiations and even increased during irradiation with 0.2 MeV protons. In a deep level transient spectroscopy (DLTS) study of the irradiated samples, the minority carrier defects H4 and H5 at E(sub v) + 0.33 and E(sub v) + 0.52 eV and the majority carrier defects E7 and El0 at E(sub c) - 0.39 and E(sub c) - 0.74 eV, were observed. The defect introduction rates for the 0.2 MeV proton irradiations were about 20 times higher than for the 10 MeV proton irradiations. The defect El0, observed here after irradiation, has been shown to act as a donor in irradiated n-type InP and may be responsible for obscuring carrier removal. The results of this study are consistent with the much greater damage produced by low energy protons whose limited range causes them to stop in the active region of the solar cell.

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study

PubMed Central

Goldman, Stewart; Yamada, Tohru; Beattie, Craig W.; Bressler, Linda; Pacini, Michael; Pollack, Ian F.; Fisher, Paul Graham; Packer, Roger J.; Dunkel, Ira J.; Dhall, Girish; Wu, Shengjie; Onar, Arzu; Boyett, James M.; Fouladi, Maryam

2016-01-01

Background p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. Methods Children aged 3–21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. Results Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. Conclusions This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose. PMID:27022131

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Corn, Paul G., E-mail: pcorn@mdanderson.org; Song, Danny Y.; Heath, Elisabeth

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles).more » A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.« less

Phase I study of intravenous (IV) docetaxel and intraperitoneal (IP) oxaliplatin in recurrent ovarian and fallopian tube cancer.

PubMed

Taylor, Sarah E; Li, Ruosha; Petschauer, Jennifer S; Donovan, Heidi; O'Neal, Sara; Keeler, Amanda W; Zamboni, William C; Edwards, Robert P; Zorn, Kristin K

2015-09-01

The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IV docetaxel and IP oxaliplatin in women with recurrent ovarian (OV), fallopian tube (FT) or peritoneal (PP) cancer. Secondary objectives included response rate, time to progression, pharmacokinetics (PK) and quality of life (QoL). Patients received docetaxel 75mg/m(2) IV day (d) 1 and oxaliplatin escalating from 50mg/m(2) IP d2 every 3weeks using a 3+3 design. Treatment continued until disease progression, remission, or intolerable toxicity. Plasma and IP samples were taken to determine drug concentrations. MD Anderson Symptom Inventory and symptom interference scale were completed weekly. Thirteen patients were included. Median number of cycles was 6 (range 1-10). Ten patients had measureable disease. Best response was partial response (PR-2), stable disease (SD-7), and progressive disease (PD-1). Twenty-one Grades 3-4 toxicities were noted, commonly hematologic. Two patients had DLTs: prolonged neutropenia (1) and abdominal pain (1). MTD was d1 docetaxel 75mg/m(2) IV and d2 oxaliplatin 50mg/m(2) IP. Symptom burden peaked week one and returned to baseline by week two of each cycle on dose level 1. Dose level 2 had persistently high symptom burden and interference. At IP oxaliplatin doses of 50mg/m(2), total unbound drug exposure (AUC) averaged 8 times larger and Cmax reached concentrations 50-fold greater in IP fluid compared to plasma. Docetaxel 75mg/m(2) IV d1 and oxaliplatin 50mg/m(2) IP d2 is the MTD. Most patients had PR or SD. Patient-reported outcomes demonstrate temporary but tolerable decrements in QoL. IP oxaliplatin provides PK advantages over IV administration. Copyright © 2015 Elsevier Inc. All rights reserved.

Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

PubMed Central

Fouladi, Maryam; Park, Julie R.; Stewart, Clinton F.; Gilbertson, Richard J.; Schaiquevich, Paula; Sun, Junfeng; Reid, Joel M.; Ames, Matthew M.; Speights, Roseanne; Ingle, Ashish M.; Zwiebel, James; Blaney, Susan M.; Adamson, Peter C.

2010-01-01

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults. PMID:20606092

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

PubMed Central

Suman, Vera J.; Goetz, Matthew; Haluska, Paul; Moynihan, Timothy; Nanda, Rita; Olopade, Olufunmilayo; Pluard, Timothy; Guo, Zhanfang; Chen, Helen X.; Erlichman, Charles; Ellis, Matthew J.; Fleming, Gini F.

2015-01-01

The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34–72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing. PMID:23605083

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

PubMed Central

Tezuka, Kenji; Takashima, Tsutomu; Kashiwagi, Shinichiro; Kawajiri, Hidemi; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

2017-01-01

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted. PMID:28413662

Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel.

PubMed

Fetterly, Gerald J; Grasela, Thaddeus H; Sherman, Jeffrey W; Dul, Jeanne L; Grahn, Amy; Lecomte, Diane; Fiedler-Kelly, Jill; Damjanov, Nevena; Fishman, Mayer; Kane, Michael P; Rubin, Eric H; Tan, Antoinette R

2008-09-15

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

PubMed

Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

2016-06-01

The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. © 2016 Wiley Periodicals, Inc.

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brade, Anthony M., E-mail: anthony.brade@rmp.uhn.on.ca; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario; Ng, Sylvia

Purpose: To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). Methods and Materials: Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated.more » Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. Results: Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level −1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. Conclusions: Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.« less

A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors.

PubMed

Jimeno, Antonio; Gordon, Michael; Chugh, Rashmi; Messersmith, Wells; Mendelson, David; Dupont, Jakob; Stagg, Robert; Kapoun, Ann M; Xu, Lu; Uttamsingh, Shailaja; Brachmann, Rainer K; Smith, David C

2017-12-15

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

PubMed

Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-07-13

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.

PubMed

Postel-Vinay, Sophie; Collette, Laurence; Paoletti, Xavier; Rizzo, Elisa; Massard, Christophe; Olmos, David; Fowst, Camilla; Levy, Bernard; Mancini, Pierre; Lacombe, Denis; Ivy, Percy; Seymour, Lesley; Le Tourneau, Christophe; Siu, Lillian L; Kaye, Stan B; Verweij, Jaap; Soria, Jean-Charles

2014-08-01

Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI. Copyright © 2014 Elsevier Ltd. All rights reserved.

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study.

PubMed

Lulla, Rishi R; Goldman, Stewart; Yamada, Tohru; Beattie, Craig W; Bressler, Linda; Pacini, Michael; Pollack, Ian F; Fisher, Paul Graham; Packer, Roger J; Dunkel, Ira J; Dhall, Girish; Wu, Shengjie; Onar, Arzu; Boyett, James M; Fouladi, Maryam

2016-09-01

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, Shilpen, E-mail: Shilpenp@uw.edu; DiBiase, Steven; Meisenberg, Barry

2012-02-01

Purpose: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. Methods and Materials: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were givenmore » tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status {>=}60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m{sup 2} divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m{sup 2} increments until the MTD was reached. When {>=}2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m{sup 2}. A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. Results: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m{sup 2}. One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m{sup 2}. Conclusions: The MTD of tamoxifen was 100 mg/m{sup 2} when given concurrently with temozolomide 75 mg/m{sup 2} and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.« less

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ben-Josef, Edgar, E-mail: edgar.ben-josef@uphs.upenn.edu; Schipper, Mathew; Francis, Isaac R.

2012-12-01

Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) wasmore » given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.« less

Synthesis of ALD zinc oxide and thin film materials optimization for UV photodetector applications

NASA Astrophysics Data System (ADS)

Tapily, Kandabara Nouhoum

Zinc oxide (ZnO) is a direct, wide bandgap semiconductor material. It is thermodynamically stable in the wurtzite structure at ambient temperature conditions. ZnO has very interesting optical and electrical properties and is a suitable candidate for numerous optoelectronic applications such as solar cells, LEDs and UV-photodetectors. ZnO is a naturally n-type semiconductor. Due to the lack of reproducible p-type ZnO, achieving good homojunction ZnO-based photodiodes such as UV-photodetectors remains a challenge. Meanwhile, heterojunction structures of ZnO with p-type substrates such as SiC, GaN, NiO, AlGaN, Si etc. are used; however, those heterojunction diodes suffer from low efficiencies. ZnO is an n-type material with numerous intrinsic defect levels responsible for the electrical and optical behaviors. Presently, there is no clear consensus about the origin of those defects. In this work, ZnO was synthesized by atomic layer deposition (ALD). ALD is a novel deposition technique suitable for nanotechnology engineering that provides unique features such as precise control of ZnO thin film with atomic resolution, high uniformity, good conformity and high aspect ratio. Using this novel deposition technique, the ALD ZnO deposition process was developed and optimized using diethyl zinc as the precursor for zinc and water vapor as the oxygen source. In order to optimize the film quality for use in electronic applications, the physical, mechanical and electrical properties were investigated. The structural and mechanical properties of the ALD ZnO thin films were investigated by X-ray diffraction (XRD), transmission electron microscopy (TEM), atomic force microscopy (AFM), scanning electron microscopy (SEM), spectroscopic Ellipsometry, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, UV-VIS absorption and nanoindentation. The electrical characterizations were performed using C-V, I-V, DLTS, Hall Effect, and four-point probe. The intrinsic defects responsible for the electrical and optical properties of the ALD ZnO films were analyzed and identified. ALD ZnO based electronic devices were fabricated, optimized and their electrical characteristics measured. The photocurrent characteristics of ALD ZnO were also optimized, and high efficiency UV-photodetectors were achieved.

Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

PubMed

DeFilipp, Zachariah; Li, Shuli; Kempner, Maria E; Brown, Jami; Del Rio, Candice; Valles, Betsy; Hunnewell, Chrisa; Saylor, Meredith; Vanderklish, Julie; Dey, Bimalangshu R; El-Jawahri, Areej; McAfee, Steven L; Spitzer, Thomas R; Chen, Yi-Bin

2018-05-11

We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3+3 study design was used with the primary endpoint to determine the maximum tolerated dose (MTD) of BV in this population. Escalating doses of BV were planned, starting with 0.6 mg/kg q3weeks (dose level 0) and increasing by 0.3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent prior to dosing. The median number of cycles of therapy was 4 (range, 1-16). Reasons for stopping therapy prematurely included toxicities (n=9), patient decision (n=3), lack of response (n=2), and death (n=1). There were 2 DLTs observed: PRES (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The MTD was not reached as the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to NIH cGVHD Response Criteria, 8 patients (47%) experienced a partial response while 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level prior to therapy was 61.5 ng/mL (range, 7.8-474.9), however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed. Copyright © 2018. Published by Elsevier Inc.

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

PubMed

Chugh, R; Griffith, K A; Davis, E J; Thomas, D G; Zavala, J D; Metko, G; Brockstein, B; Undevia, S D; Stadler, W M; Schuetze, S M

2015-07-01

Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. ClinicalTrials.gov:NCT00789633. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Inflation of the distal cuff by saline reduces the incidence of malposition of the bronchial tube during lung separation in patients receiving nitrous oxide.

PubMed

Suzuki, Manzo; Haraguchi, Shuji; Kitamura, Akira; Shimada, Yoichi; Sakamoto, Atsuhiro

2007-12-01

A common problem during lung separation is malposition of the double-lumen tube (DLT). It was hypothesized that inflation of the distal cuff with saline instead of air may reduce the incidence of malposition of the endobronchial tube. Fifty-two patients who were scheduled to undergo thoracic surgery with lung separation by a DLT were randomly assigned to 1 of 2 groups: the distal cuff was inflated with 2 mL of air in the air group (n = 26), whereas the distal cuff was inflated with 1.2 mL of saline in the saline group (n = 26). Anesthesia was maintained by isoflurane, 50% oxygen and nitrous oxide mixture, and incremental injection of epidural ropivacaine, 0.75%. Respiration was controlled by pressure-controlled ventilation. The peak airway pressure was maintained between 20 to 25 cmH2O. The position of the bronchial cuff was evaluated with a fiberoptic bronchoscope just after intubation and 1 and 2 hours after intubation by using a 3-point scale: 0, in exactly the same position as the previous inspection; 1, not in exactly the same position as that in the previous inspection, but there was no possibility that the tube was malpositioned; and 2, the cuff looked as if it was going to become herniated or dislodged. Signs suggesting malposition such as air leakage, high airway pressure, or inflation of the independent lung were recorded. When repositioning was required, the anesthesiologist repositioned the DLT using bronchoscopic observation or clinical signs. The endpoint of this study was the number of patients who required repositioning during surgery. The malposition score at 1 hour and 2 hours after intubation was comparable in the 2 groups (0.6 +/- 0.6 v 0.4 +/- 0.6 and 0.5 +/- 0.8 v 0.2 +/- 0.5, mean +/- standard deviation, air group v saline group, 1 hour and 2 hours after positioning, p = 0.27 and p = 0.33, respectively). However, a significantly higher cumulative number of air-group patients required repositioning of the tube than saline-group patients (13:6, air group:saline group, p = 0.04). Inflation of the distal cuff with saline may reduce the incidence of malpositioning of DLTs during lung separation.

FOREWORD Foreword

NASA Astrophysics Data System (ADS)

Kuriplach, Jan; Procházka, Ivan

2011-01-01

The 6th International Workshop on Positron Studies of Defects (PSD) took place in Prague, Czech Republic, from September 1 to 5, 2008. It was hosted by the Faculty of Mathematics and Physics of the Charles University in Prague. The PSD Workshop brought together positron scientists interested in studying various defects in mainly crystalline materials, and provided an opportunity to report on new results and achievements as well as on novel experimental and theoretical methods in this field. The workshop topics can be characterized as follows: Defect formation, migration, agglomeration and annealing Momentum distribution studies of defects: Doppler broadening, angular correlation of annihilation radiation (ACAR) Slow positron beam studies of defects at surface and near surface regions Theoretical calculations and simulations of momentum distributions, positron lifetimes and other characteristics for defects Defects in unusual materials: quasicrystals, nanostructures Advances in positron experimental methods applicable to defect studies Complementary experimental methods in defect studies (TEM, XRD, AP, SANS, DLTS, PL and others) Industrial applications of positron defect studies The first PSD workshop was organized in Wernigerode, Germany in 1987. The next four workshops were held in Halle, Germany (1994), Hamilton, ON, Canada (1999), Sendai, Japan (2002) and Pullman, WA, USA (2004) under the name Positron Studies of Semiconductor Defects (PSSD). As studying defects in metals is once again gaining importance - as is also documented in these Proceedings - the name of the Workshop in Prague was changed to the original version PSD. The PSD workshops will be organized every three years and the next one will be held in Delft, The Netherlands at the turn of August and September, 2011. We would like to express our gratitude to all of the workshop participants for their presentations and contributions to discussions, which made the PSD Workshop a successful scientific event. In total 65 scientists and students from 15 countries took part in the PSD Workshop. The workshop programme comprised 24 invited lectures, 19 contributed talks and 22 posters. Thirty contributions are included in these Proceedings, covering various aspects of positron defect studies. In particular, proceedings papers are divided into five categories: defects in semiconductors, defects in metals, nanostructures, larger free volumes and experimental apparatus including data evaluation. For the previous PSD/PSSD workshops proceedings were not published on a regular basis and, hopefully, these Proceedings will be the start of a new tradition. Jan Kuriplach Ivan Procházka Editors

Solar Cell Fabrication Studies Pertinent to Developing Countries.

NASA Astrophysics Data System (ADS)

Prah, Joseph Henry

That there is a need in the world today, and in the Third World in particular, for developing renewable energy sources is a proposition without question. Toward that end, the harnessing of solar energy has attracted much attention recently. In this thesis, we have addressed the question of Photovoltaics among the many approaches to the problem as being of poignant relevance in the Third World. Based on our studies, which involved the physics of solar cells, various solar cell configurations, the materials for their fabrication and their fabrication sequences, we arrived at the conclusion that silicon homojunction solar cells are best suited to the present needs and environment of, and suitable for development in the Third World, though Cadmium Sulphide-Cuprous Sulphide solar cell could be considered as a viable future candidate. Attendant with the adoption of photovoltaics as electric energy supply, is the problem of technology transfer and development. Towards that goal, we carried out in the laboratory, the fabrication of solar cells using very simple fabrication sequences and materials to demonstrate that tolerable efficiencies are achievable by their use. The view is also presented that for a thriving and viable solar cell industry in the Third World, the sine qua non is an integrated national policies involving all facets of solar cell manufacture and application, namely, material processing and fabrication, basic research, and development and socio -economic acceptance of solar cell appliances. To demonstrate how basic research could benefit solar cell fabrication, we undertook a number of experiments, such as varying our fabrication sequences and materials, finding their radiation tolerance, and carrying out Deep Level Transient Spectroscopy (DLTS) studies, in an attempt to understand some of the fabrication and environmental factors which limit solar cell performance. We thus found that subjecting wafers to preheat treatments does not improve solar cell performance, but rather reduces solar cell radiation tolerance. Also P-type substrate solar cells were found to be more radiation resistant than N-type substrate solar cells. The Deep Level Transient Spectroscopy results showed that carbon and oxygen, as one would expect, are chief contaminants of the silicon wafers that we used in the fabrication of our solar cells. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of author.) UMI.

Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide).

PubMed

Xia, Chang; Leon-Ferre, Roberto; Laux, Douglas; Deutsch, Jeremy; Smith, Brian J; Frees, Melanie; Milhem, Mohammed

2014-10-01

To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy. A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent. Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia (30%), neutropenia (23%), nausea (23%), and lymphopenia (18%). The most common reason for study discontinuation was disease progression. This triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

Comparison of a tube-holder (Rescuefix) versus tape-tying for minimizing double-lumen tube displacement during lateral positioning in thoracic surgery

PubMed Central

Byun, Sung Hye; Kang, Su Hwang; Kim, Jong Hae; Ryu, Taeha; Kim, Baek Jin; Jung, Jin Yong

2016-01-01

Abstract Background: Double-lumen endotracheal tubes (DLTs) are often displaced during change from the supine to the lateral decubitus position. The aim of this study was to determine whether Rescuefix, a recently developed tube-holder device, is more effective than the traditional tape-tying method for tube security during lateral positioning. Methods: Patients were randomly assigned to a Rescuefix (R) group (n = 22) or a tape (T) group (n = 22). After intubation with a left-sided DLT and adjustment of the appropriate DLT position using a fiberoptic bronchoscope, the DLT was fixed firmly at the side of the mouth by either Rescuefix or Durapore tape. “Tracheal depth” (from the tracheal carina to the elbow connector of the DLT) and “bronchial depth” (from the left bronchial carina to the elbow connector of the DLT) were measured in the supine position using the fiberoptic bronchoscope. After positional change, tracheal and bronchial depths were measured as described above. As the primary endpoint, displacement of the DLT during positional change was evaluated by obtaining the difference in depths measured when the patient was in the supine and lateral decubitus positions. In addition, after lateral positioning of the patient, any requirement for repositioning the DLT was recorded. Results: After lateral positioning, there were no significant differences in changes in tracheal and bronchial depths between the groups (tracheal depth 6.1 ± 4.4 mm [R group] and 9.1 ± 5.6 mm [T group], P = 0.058; bronchial depth 6.5 ± 4.4 mm [R group], and 8.5 ± 4.6 mm [T group], P = 0.132). Although the amount of change in tracheal and bronchial depths was not different between the groups, the need to reposition the DLT was significantly lower in the R group than in the T group (32% vs 68%, P = 0.016). Conclusion: This study demonstrated that use of Rescuefix did not reduce the amount of DLT displacement, but it did significantly lower the incidence of DLT repositioning compared with the tape-tying method. Therefore, Rescuefix appears to be an effective alternative to minimizing DLT displacement during lateral positioning in thoracic surgery. Trial registration: http://cris.nih.go.kr identifier: KCT0001949. PMID:27495093

Recovery of Electron/Proton Radiation-Induced Defects in n+p AlInGaP Solar Cell by Minority-Carrier Injection Annealing

NASA Technical Reports Server (NTRS)

Lee, H. S.; Yamaguchi, M.; Elkins-Daukes, N. J.; Khan, A.; Takamoto, T.; Imaizumi, M.; Ohshima, T.; Itoh, H.

2007-01-01

A high efficient In0.48Ga0.52P/In0.01Ga0.99As/Ge triple junction solar cell has been developed for application in space and terrestrial concentrator PV system [1-3]. Recently, a high conversion efficiency of 31.5% (AM1.5G) has been obtained in InGaP/(In)GaAs/Ge triple junction solar cell, and as a new top cell material of triple junction cells, (Al)InGaP [1] has been proposed to improve the open-circuit voltage (Voc) because it shows a higher Voc of 1.5V while maintaining the same short-circuit current (ISC) as a conventional InGaP top cell under AM1.5G conditions as seen in figure 1 (a). Moreover, the spectral response of 1.96eV AlInGaP cell with a thickness of 2.5..m shows a higher response in the long wavelength region, compared with that of 1.87eV InGaP cell with 0.6..m thickness, as shown in figure 1 (b). Its development will realize next generation multijunction (MJ) solar cells such as a lattice mismatched AlInGaP/InGaAs/Ge 3-junction and lattice matched AlInGaP/GaAs/InGaAsN/Ge 4-junction solar cells. Figure 2 shows the super high-efficiency MJ solar cell structures and wide band spectral response by MJ solar cells under AM1.5G conditions. For realizing high efficient MJ space solar cells, the higher radiation-resistance under the electron or proton irradiation is required. The irradiation studies for a conventional top cell InGaP have been widely done [4-6], but little irradiation work has been performed on AlInGaP solar cells. Recently, we made the first reports of 1 MeV electron or 30 keV proton irradiation effects on AlInGaP solar cells, and evaluated the defects generated by the irradiation [7,8]. The present study describes the recovery of 1 MeV electron / 30 keV proton irradiation-induced defects in n+p- AlInGaP solar cells by minority-carrier injection enhanced annealing or isochronal annealing. The origins of irradiation-induced defects observed by deep level transient spectroscopy (DLTS) measurements are discussed.

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

PubMed

Riedel, Richard F; Meadows, Kellen L; Lee, Paula H; Morse, Michael A; Uronis, Hope E; Blobe, Gerard C; George, Daniel J; Crawford, Jeffrey; Niedzwiecki, Donna; Rushing, Christel N; Arrowood, Christy C; Hurwitz, Herbert I

2017-03-01

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors. This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m 2 (cohort 1) or 480 mg/m 2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles. Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m 2 TH-302 cohort and 6 patients in the 480 mg/m 2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m 2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m 2 TH-302 cohort. The 340 mg/m 2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11). The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m 2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Extended defects and hydrogen interactions in ion implanted silicon

NASA Astrophysics Data System (ADS)

Rangan, Sanjay

The structural and electrical properties of extended defects generated because of ion implantation and the interaction of hydrogen with these defects have been studied in this work. Two distinct themes have been studied, the first where defects are a detrimental and the second where they are useful. In the first scenario, transient enhanced diffusion of boron has been studied and correlated with defect evolution studies due to silicon and argon ion implants. Spreading resistance profiles (SRP) correlated with deep level transient spectroscopy (DLTS) measurements, reveal that a low anneal temperatures (<650°C) defect dissolution and defect injection dominates, resulting in increased junction depths. At higher anneal temperatures, however, repair dominates over defect injection resulting in shallower junctions. Hydrogenation experiments shows that hydrogen enhances dopant activation and reduces TED at low anneal temperatures (<550°C). At anneal temperatures >550°C, the effect of hydrogen is lost, due to its out-diffusion. Moreover, due to catastrophic out-diffusion of hydrogen, additional damage is created resulting in deeper junctions in hydrogenated samples, compared to the non-hydrogenated ones. Comparing defect evolution due to Si and Ar ion implants at different anneal temperatures, while the type of defects is the same in the two cases, their (defect) dissolution occurs at lower anneal temperatures (˜850°C) for Si implants. Dissolution for Ar implants seems to occur at higher anneal temperatures. The difference has been attributed to the increased number of vacancies created by Ar to that of silicon implant. In second aspect, nano-cavity formation due to vacancy agglomeration has been studied by helium ion implantation and furnace anneal, where the effect of He dose, implant energy and anneal time have been processing parameters that have been varied. Cavities are formed only when the localized concentration of He is greater than 3 x 1020 cm-3. While at high implant doses, a continuous cavity layer is formed, at low implant doses a discontinuous layer is observed. The formation of cavities at low doses has been observed for the first time. Variation of anneal times reveal that cavities are initially facetted (for short anneal times) and tend to become spherical when annealed for along time (300min). Also presented is the recipe for formation of multiple cavity layers and the electrical and optical properties of these cavities. Electrically, these cavities are metastable, with two strong minority carrier peaks formed by multiple defect levels. Photoluminescence measurements reveal a strong 0.8eV photon peak.

CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.

PubMed

Seto, Takashi; Kiura, Katsuyuki; Nishio, Makoto; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yamamoto, Nobuyuki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Takeuchi, Kengo; Shimada, Tadashi; Tanaka, Tomohiro; Tamura, Tomohide

2013-06-01

Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. Chugai Pharmaceutical Co, Ltd. Copyright © 2013 Elsevier Ltd. All rights reserved.

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma.

PubMed

Lowery, Maeve A; Yu, Kenneth H; Kelsen, David Paul; Harding, James J; Bomalaski, John S; Glassman, Danielle C; Covington, Christina M; Brenner, Robin; Hollywood, Ellen; Barba, Adalberto; Johnston, Amanda; Liu, Kay Chia-Wei; Feng, Xiaoxing; Capanu, Marinela; Abou-Alfa, Ghassan K; O'Reilly, Eileen M

2017-12-01

ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1. A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m 2 weekly (cohort 1) or at 36 mg/m 2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m 2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. © 2017 American Cancer Society. © 2017 American Cancer Society.

Naval Research Laboratory's programs in advanced indium phosphide solar cell development

NASA Technical Reports Server (NTRS)

Summers, Geoffrey P.

1995-01-01

The Naval Research Laboratory has been involved in developing InP solar cell technology since 1988. The purpose of these programs was to produce advanced cells for use in very high radiation environments, either as a result of operating satellites in the Van Allen belts or for very long duration missions in other orbits. Richard Statler was technical representative on the first program, with Spire Corporation as the contractor, which eventually produced several hundred, high efficiency 2 x 2 sq cm single crystal InP cells. The shallow homojunction technology which was developed in this program enabled cells to be made with AMO, one sun efficiencies greater than 19%. Many of these cells have been flown on space experiments, including PASP Plus, which have confirmed the high radiation resistance of InP cells. NRL has also published widely on the radiation response of these cells and also on radiation-induced defect levels detected by DLTS, especially the work of Rob Walters and Scott Messenger. In 1990 NRL began another Navy-sponsored program with Tim Coutts and Mark Wanlass at the National Renewable Energy Laboratory (NREL), to develop a one sun, two terminal space version of the InP-InGaAs tandem junction cell being investigated at NREL for terrestrial applications. These cells were grown on InP substrates. Several cells with AM0, one sun efficiencies greater than 22% were produced. Two 2 x 2 sq cm cells were incorporated on the STRV lA/B solar cell experiment. These were the only two junction, tandem cells on the STRV experiment. The high cost and relative brittleness of InP wafers meant that if InP cell technology were to become a viable space power source, the superior radiation resistance of InP would have to be combined with a cheaper and more robust substrate. The main technical challenge was to overcome the effect of the dislocations produced by the lattice mismatch at the interface of the two materials. Over the last few years, NRL and Steve Wojtczuk at Spire have been developing a single junction InP on Si cell, in an ONR-sponsored SBIR program. Both cell polarities were investigated and the best efficiencies to date (approximately 13% on a 2 x 4 sq cm cell) were achieved with n/p cells. Earlier this year NRL began a program with ASEC to develop a two terminal InP-InGaAs tandem cell on a Ge substrate. RTI and NREL are subcontractors on this program. The results of an ONR-sponsored study of the potential market for InP/Si cells will be discussed. Also the technical status of both the InP/Si and the InP-InGaAs/Ge programs will be given. The technical challenges still remaining will be briefly described.