Effect of substrate temperature on the optoelectronic properties of DC magnetron sputtered copper oxide films

Copper oxide thin films are deposited on quartz substrates by DC magnetron sputtering and the effect of deposition temperature on their optoelectronic properties is examined in detail. Scanning Electron Microscopy (SEM), X-ray diffraction (XRD) analysis, Raman spectroscopy, UV-Vis spectroscopy, and four-probe sheet resistance measurements are used to characterize the surface morphology, structural, optical, and electrical properties respectively. Deposition is carried out at room temperature and between 200 and 300 {\deg}C. XRD analysis indicates that the oxide formed is primarily Cu$_2$O and the absorption spectra show the films have a critical absorption edge at around 300 nm. The sheet resistance gradually decreases with increase in deposition temperature thereby increasing the conductivity of these thin films. Also observed is the increase in band gap from 2.20 eV for room temperature deposition to 2.35 eV at 300 {\deg}C. The optical band gap and the variation of sheet resistance with temperature shows that the microstructure plays a vital role in their behavior. These transformation characteristics are of huge technological importance having variety of applications including transparent solar cell fabrication.Comment: 9 pages, 4 figures, and 2 table

Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas

Background: LEE011 is an oral small molecule inhibitor with highly specific nanomolar inhibitory activity against CDK4/cyclinD1 and CDK6/cylinD3 complexes. Preclinical studies with LEE011 have demonstrated robust anti-tumor activity in several tumor models with functional retinoblastoma protein (pRb). Methods: The primary objective this phase 1 dose escalation study was to determine the maximum tolerated dose (MTD) based on cycle 1 dose-limiting toxicities (DLTs) and establish the recommended dose for expansion (RDE) of LEE011 in patients (pts) with pRb-positive advanced solid tumors or lymphomas. Using a Bayesian logistic regression model with overdose control principle, escalating doses of LEE011 were administered daily for 21 days of 28-day cycles. Following MTD determination, a continuous dosing schedule was also evaluated. Evaluation of safety and pharmacokinetics (PK) from all pts contributed to defining the RDE. Results: As of June 28, 2013, a total of 70 pts were treated in the escalation phase at doses from 50-1200 mg. DLTs are described in the table. MTD was defined at 900 mg on a 21 of 28-day dosing schedule. Additional patients were treated at 750 mg and 600 mg on the current schedule and at 600 mg on a continuous schedule to define the RDE and sustain optimal long-term dosing. Following review of PK and safety data, including AEs observed beyond cycle 1, the planned RDE is 600 mg for 21 days of a 28-day treatment cycle. Common adverse events (AEs) were gastrointestinal (nausea 40%, diarrhea 30%) and hematologic (anemia 43%, neutropenia 40%); the majority of AEs were grades 1/2 and reversible. Asymptomatic QTc prolongation was observed at the higher doses. LEE011 is absorbed orally with Tmax ≈ 4 hours and effective t1/2 ≈24 hours. Dose-dependent increases in exposure were observed. Preliminary evidence of activity was observed including stable disease for ≥ 6 cycles in 10/70 pts (14%) and 1 confirmed partial response in a pt with ER-positive breast cancer. Preliminary tumor pharmacodynamic data shows evidence of modulation at doses of 600 mg and above. Conclusions: LEE011, a highly selective inhibitor of CDK4/6, exhibited an acceptable safety profile, dose dependent PK, and preliminary clinical activity. Enrollment will continue in the expansion phase. (Figure presented)

A phase i study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results: Among 132 patients, 125 received ribociclib 3- weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications

Preclinical therapeutic synergy of MEK1/2 and CDK4/6 inhibition in neuroblastoma

Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies. Results: Sensitivity to binimetinib and ribociclib was inversely related (r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs. Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed highrisk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors. Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK. Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m(2). Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m(2); n = 1) or grade 4 thrombocytopenia (470 mg/m(2); n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/ 38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m(2) [equivalent to 600 (RP2D)-900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively. Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m(2)) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. (C) 2017 AACR