ALBERT

Description: Journal of the American Chemical Society DOI: 10.1021/ja408550a

Description: We present optical spectra of the nearby Type Ia supernova SN 2011fe at 100, 205, 311, 349 and 578 d post-maximum light, as well as an ultraviolet (UV) spectrum obtained with the Hubble Space Telescope at 360 d post-maximum light. We compare these observations with synthetic spectra produced with the radiative transfer code phoenix. The day +100 spectrum can be well fitted with models that neglect collisional and radiative data for forbidden lines. Curiously, including these data and recomputing the fit yields a quite similar spectrum, but with different combinations of lines forming some of the stronger features. At day +205 and later epochs, forbidden lines dominate much of the optical spectrum formation; however, our results indicate that recombination, not collisional excitation, is the most influential physical process driving spectrum formation at these late times. Consequently, our synthetic optical and UV spectra at all epochs presented here are formed almost exclusively through recombination-driven fluorescence. Furthermore, our models suggest that the UV spectrum even as late as day +360 is optically thick and consists of permitted lines from several iron-peak species. These results indicate that the transition to the ‘nebular’ phase in Type Ia supernovae is complex and highly wavelength dependent.

Description: Herein we analyse late-time (post-plateau; 103 〈 t 〈 1229 d) optical spectra of low-redshift (z 〈 0.016), hydrogen-rich Type IIP supernovae (SNe IIP). Our newly constructed sample contains 91 nebular spectra of 38 SNe IIP, which is the largest data set of its kind ever analysed in one study, and many of the objects have complementary photometric data. The strongest and most robust result we find is that the luminosities of all spectral features (except those of helium) tend to be higher in objects with steeper late-time V-band decline rates. A steep late-time V-band slope likely arises from less efficient trapping of γ-rays and positrons, which could be caused by multidimensional effects such as clumping of the ejecta or asphericity of the explosion itself. Furthermore, if γ-rays and positrons can escape more easily, then so can photons via the observed emission lines, leading to more luminous spectral features. It is also shown that SNe IIP with larger progenitor stars have ejecta with a more physically extended oxygen layer that is well-mixed with the hydrogen layer. In addition, we find a subset of objects with evidence for asymmetric 56Ni ejection, likely bipolar in shape. We also compare our observations to theoretical late-time spectral models of SNe IIP from two separate groups and find moderate-to-good agreement with both sets of models. Our SNe IIP spectra are consistent with models of 12–15 M⊙ progenitor stars having relatively low metallicity (Z ≤ 0.01).

Description: SNS-595 is a novel naphthyridine analog, a class of compounds not previously used for cancer treatment. SNS-595 is currently in an escalating-dose phase 1 trial in acute leukemia and several phase 2 studies in solid tumors. SNS-595 has a unique mechanism of action; causing double-strand breaks during S phase that are solely repaired through a DNA-PK-dependent pathway. This damage induces DNA damage-repair signals through both p53 and p73 pathways during DNA synthesis and is accompanied by a rapid onset of apoptosis and an irreversible G2 arrest. This mechanism suggests that SNS-595 could interact in combination favorably with other DNA damaging agents that utilize different mechanisms of damage signaling and repair. SNS-595 demonstrates potent anti-proliferative effects on human leukemic cell lines in vitro and is active in LM-3 Jck and CCRF-CEM hematologic xenograft models. Previously, we have shown that administration of SNS-595 results in a dose dependent loss in bone marrow cellularity and reduction in circulating neutrophils in mice (Proc. Amer. Assoc. Cancer. Res.47: 4726, 2006). These data suggest that SNS-595 activity in bone marrow and circulating blood may provide a therapeutic rationale for the treatment of acute leukemias and advanced chronic myelogenous leukemia. In this study we evaluated the effects of SNS-595 on peripheral white blood cells and bone marrow cellularity as a single agent and in combination with cytarabine (Ara-C) and daunorubicin (DNR). SNS-595 dosed once a day at 10 mg/kg IV as a single agent and Ara-C dosed three times a day as a single agent at 20 mg/kg SC, on day 0 and 4, resulted in 44% and 12% reductions in cellularity, respectively. In contrast, combination dosing of SNS-595 once a day at 10 mg/kg IV with Ara-C dosed three times a day at 20 mg/kg SC resulted in a 93% reduction in cellularity. Normal cellularity recovered on Day 12 (8 days post last dose). Furthermore, the SNS-595/Ara-C combination reduced cellularity more than Ara-C dosed at the MTD of 60 mg/kg three times a day SC (42% reduction in cellularity). Circulating leukocyte levels were also reduced including neutrophils that dropped from 1359 cells/ml to 587 cells/ml for SNS-595 dosed at 10 mg/kg IV and 1212 cells/ml for Ara-C dosed three times a day at 20 mg/kg SC on day 8. The co-administration of these two doses resulted in a near elimination of circulating neutrophils (29 cells/ml). Leukocyte counts subsequently returned to normal levels by Day 18 (14 days post last dose). In conclusion, co-administration of SNS-595 and Ara-C reversibly ablates murine bone marrow cells and reversibly depletes circulating neutrophils. These data indicate that SNS-595 has the potential to combine effectively with Ara-C for the treatment of acute leukemias and suggests that additional studies in patients with advanced hematologic malignancies are warranted.

Description: Abstract 2457 Background: Standard vincristine sulfate (VCR) plasma pharmacokinetics (PK) is described by a bi-exponential profile with a very short half-life followed by a longer elimination half-life; the volume of distribution is large, suggesting wide and diffuse distribution and perhaps tissue binding. These PK characteristics may limit optimal therapeutic activity of VCR by limiting Cmaxand drug exposure in target tissues involved with cancer. VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo) is a sphingomyelin- and cholesterol-based nanoparticle formulation of VCR that was designed to be different from and overcome the dosing and pharmacokinetic limitations of standard VCR. The objectives for development of VSLI were to: 1) increase the plasma circulation time; 2) increase tumor tissue delivery by preferential extravasation from fenestrated (“leaky”) vasculature; 3) accumulation in tumor tissues; and 4) slow release of VCR in tumor tissues instead of the systemic circulation. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome negative ALL and is in development for pediatric ALL and aggressive NHL. Methods: The PK and tissue distribution of VCR was evaluated in Sprague-Dawley rats following a single IV bolus dose (2.0 mg/m2) of VSLI or VCR, utilizing 3H-VCR as a marker. The tissue levels of total VCR were measured for up to 72 hours post-dose. PK analysis was performed using noncomparmental methods with the WinNonlin software package. Results: The PK profile and calculated parameters of VSLI in rats showed a substantially lower total vincristine clearance (CL) and volume of distribution (Vdz) and correspondingly greater area under the plasma concentration versus time curve (AUC) compared to standard VCR. VSLI has a long circulation time and remains in the plasma instead of being widely distributed in tissues. For most tissues from VSLI treated animals, tissue to plasma concentration ratios increased over time and peaked at 72 h after VSLI injection, indicating progressive accumulation of radiolabeled drug from plasma into the tissues. The rank order of tissues based on Cmax demonstrated that total VCR concentrations in MPS tissues (i.e., spleen, liver, lymph nodes and bone marrow) and in ovaries were substantially higher than in other organs or tissues. The lowest radioactivity levels were observed in brain, spinal cord, nerves and muscle. Higher exposures, as measured by AUCinf, of VCR were observed in plasma (83 fold), spleen (12 fold), lymph nodes (10 fold), liver (4 fold) and bone marrow (2 fold) following a radiolabeled dose of VSLI compared to VCR. Conclusion: The long circulation time and small, 100 nm, mean nanoparticle size of VSLI facilitate extravasation from fenestrated vasculature and accumulation in tissues involved in hematologic malignancies such as lymph nodes, bone marrow and spleen. Slow release of VCR in target tissues following administration of VSLI results in higher and prolonged tissue drug levels providing superior drug delivery to tissues than the same doses of standard formulation of VCR. Disclosures: Silverman: Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

Description: SNS-595 is a novel, cell cycle active cytotoxic naphthyridine analog that induces G2 arrest in a variety of preclinical tumor models. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (arm A) or twice weekly x 2 bolus (arm B), in patients with advanced or refractory acute leukemias. Objectives: The primary objectives were to:establish safety, tolerability, and MTD of SNS-595 given on each schedule,characterize pharmacokinetics (PK) of SNS-595 when given on these schedules. Secondary objectives were:assessment of clinical activity,exploration of potential biomarkers. Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (arm A) or days 1, 4, 8, 11 (arm B). Minimum cycle length was 42 days (arm A) and 39 days (arm B). Additional cycles were permitted if patients achieved stable disease or better. The starting dose was 18 mg/m2/d on arm A, and 9 mg/m2/d on arm B and escalated by cohort using a modified Fibonacci schema. PK analyses for SNS-595 were performed on plasma samples collected during cycle 1. Pretreatment peripheral blood and bone marrow aspirate samples were collected for exploratory analyses of the level and functional activity of the DNA damage repair proteins DNA-PK and MSH2. Results: To date, 21 patients have been enrolled and are evaluable in the live database, including 13 patients assigned to arm A and 8 assigned to arm B, 12 males and 9 females with a median age of 64 years. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease refractory to or relapsed from prior therapy (median 3 prior regimens (range 1–6)). Dose escalation has proceeded to 50 mg/m2/d (arm A) and 19 mg/m2/d (arm B). No dose-limiting toxicities have been observed to date. Non-dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis . Grade 4 neutropenic fever was observed in only one patient. Plasma exposures at the first two dose levels in each arm increased linearly, resulting in AUCs of 5.5 – 17.8 ughr/mL for 9–27 mg/m2 doses. CL, Vss, and terminal half-lives were similar to those reported previously in solid tumor patients, and averaged ~2 L/hr/m2, 58 L/m2, and 23 hr, respectively. No patients have achieved complete response to date, although 6 patients (distributed across all dosing groups) experienced 〉50% reductions in peripheral blasts following cycle 1. Conclusion: SNS-595 appears to be well-tolerated in patients with advanced leukemias, with preliminary and promising signs of clinical activity as measured by decreases in leukemic blasts. Bone marrow ablation has not yet been achieved; patient accrual and dose-escalation are ongoing.