Abstract: Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged & gt;60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults & gt;60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

Abstract: BACKGROUND: Angiogenesis is increasingly known to play a role in pathogenesis of hematologic malignancies, including myeloid neoplasms. Regorafenib is a multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases including VEGF- 1, 2, 3, TIE-2, PDGFR-β,c-KIT, rRET, RAF-1, FGFR-1, BRAF and p38 MAP kinase. As a result of regorafenib's broad inhibition of kinases and its effects on angiogenesis, this drug has the potential to overcome the limitations of more selective kinase inhibitors and may be associated with efficacy in various myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). METHODS: We conducted a single-center, open-label, dose-escalation and expansion phase I trial in patients with relapsed/refractory AML, MPN, or MDS to assess the safety, tolerability, and preliminary efficacy of regorafenib and identify the recommended phase 2 dose (RP2D). A 3+3 dose escalation design was used with 2 planned dose levels (120 mg or 160 mg daily in 28-day cycles), as well as 1 de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. RESULTS: Six patients were enrolled during the dose escalation phase (3 at 120 mg daily followed by 3 at 160 mg daily), with no DLTs, as defined by a Grade & gt;3 toxicity occurring within the first 28 days after initiation of treatment, and unrelated to the myeloid neoplasm. Therefore, the RP2D of regorafenib was identified as 160 mg daily. Ten additional patients were enrolled on this dose during the expansion phase. The median age was 74 (range 36-84), and 13 (81%) patients were male. Diagnoses included 7 AML, 6 MDS, and 3 MPN patients (Table 1). Dose modifications and delays occurred in 5 and 4 patients, respectively. The median duration of treatment was 56 days or 2.5 cycles (range: 5-410 days, 1-15 cycles). Of the 16 patients, the best overall disease response as measured by IWG criteria included partial remission (in 1 patient with AML), stable disease in 12 (2 de novo AML, 2 secondary AML, 3 MPN, and 5 MDS) patients, and progressive disease in 3 (1 MDS and 2 secondary AML) patients. An initial improvement in absolute neutrophil count and/or hemoglobin was observed in the 6 MDS patients, although this did not meet criteria for hematologic improvement by IWG criteria. All patients have discontinued off treatment. The most frequent Grade 3-4 adverse effects (AEs) included liver function test abnormalities (5.1%), fatigue (4.3%), thrombocytopenia (3.4%), and neutropenia (3.4%) (Table 2). The majority of AEs were grades 1-2. CONCLUSIONS: Regorafenib demonstrates an acceptable safety profile in relapsed/refractory myeloid malignancy patients, a population where few treatment options exist. The majority of patients achieved stable disease. Modest improvements in cell counts were observed in MDS patients, and we are performing correlative studies to clarify regorafenib's mechanism of action and identify populations which may benefit from treatment. Disclosures Amrein: AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fathi:Kura Oncology: Consultancy; Trillium: Consultancy; Boston Biomedical: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Blueprint: Consultancy; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Newlink Genetics: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy, Research Funding. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Neuberg:Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Celgene: Research Funding. Chen:Takeda: Consultancy; Magenta: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy. Hobbs:Merck: Research Funding; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Jazz: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Bayer: Research Funding. OffLabel Disclosure: Regorafenib was used to assess safety and preliminary efficacy in advanced myeloid malignancies

Abstract: The high photo responsive property and flexibility of tailoring the optical properties of the semiconducting layered transition metal dichalcogenides are appealing and makes them potentially suitable for the optoelectronic and photo detecting applications. In the present study molybdenum, diselenide (MoSe 2 ) crystals were grown by direct vapor transport (DVT) technique in a dual zone horizontal furnace. To affirm the elemental composition and stoichiometric proportion of the as grown crystals, energy dispersive analysis of the x-ray was adopted. The surface morphological features of the grown crystals were investigated using light microscopy and scanning electron microscopy that attested the multilayer growth of crystals. The presence of single-crystalline phase and hexagonal structure was ascertained by employing transmission electron microscopy. The direct optical energy band gap of 1.42 eV was determined by UV-Visible spectroscopy. The Raman spectroscopy analysis carried out on the grown crystals revealed the presence of an A 1g mode of vibration. Photo-detecting properties of the multilayer MoSe 2 crystals were studied by exposing the basal plane of the photo-detecting sample by the polychromatic source of 70 mW/cm 2 intensity at different biasing voltages from 1 V to 5 V respectively. The eminent sensing properties of the grown multilayered crystals are unveiled by the high photo responsivity 58.2 mA/Wm 2 and specific detectivity 2.12 × 10 7 Jones. The effect of biasing voltage was prominently seen in the rise of photocurrent and detecting properties MoSe 2 crystals.

Abstract: The structural, electronic, dynamical and thermodynamical properties of binary Zr-Al alloy (Zr 3 Al) with its end members are studied using the first principles calculations based on density functional theory. We have employed the Perdew-Zunger local density approximation as the exchange correlational functional in these calculations. There is a good agreement between present and available and experimental and other theoretical data. The calculated electronic band structure and density of states suggest that the Zr-Al alloy and its end members are metallic in nature consistent with earlier studies. Full phonon dispersion curves and phonon density of states are also calculated which show the dynamical stability of these compounds at zero pressure. The temperature dependence of the thermodynamical functions are also presented.