MYRX will present the following abstracts at ASCO June 4th, 2011:
Abstract 2088 describes the results from the second cohort of a single-agent Azixa phase 2 study in recurrent gliobastoma (GBM). Results from patients who had previously failed Avastin (bevacizumab) have been previously disclosed and are summarized on the MYRX research page. In this group, 31 pts completed a median of 2 cycles of Azixa therapy, which was well tolerated. 14% of pts were progression free at 6 months, with median PFS of 1.8 months and median OS of 9.9 months. 3 PR's and 7 SD's (median 3.9 months) were observed for a clinical benefit rate of 32%- described as "modest activity". These data are all better than seen in Avastin-experienced patients.
Abstract 10529 shows preclinical xenograft data demonstrating the activity of cancer metabolism inhibitor MPC-9528 in several different dosing schemes.
Saturday June 4th Poster Presentation Abstract #2088
"Phase II study of verubulin (MPC-6827) for the treatment of subjects with recurrent glioblastoma naïve to treatment with bevacizumab."
Lyndon J. Kim, MD
Background: Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieves high brain concentration relative to plasma in animals.
Methods: Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 6 -month progression-free survival (PFS -6). Eligible subjects had a KPS "e 60, were free of active cardiovascular disease and uncontrolled hypertension and had no prior treatment with angiogenic inhibitors. Verubulin was administered at 3.3mg/m2 as a 2-hour IV infusion once weekly for 3 consecutive weeks in a 4-week cycle. Response was assessed using the Macdonald criteria. The planned sample size was thirty-four subjects.
Results: 31 adults were treated (20 men; 11 women). All subjects had prior tumor resection, a median of two chemotherapies (up-front with RT and salvage); the majority were in first relapse (77%). Median age and KPS were 56 years (range 23 -74) and 90 (range 70 -100), respectively. Median number of verubulin cycles completed was 2 (range 0 -12); one subject remains on treatment. The most common adverse events were fatigue (19%), nausea (10%) and constipation (6%). One subject discontinued the study due to a grade 2 ventricular arrhythmia. Another subject with significant cardiovascular risk factors had a non-fatal myocardial infarction. 3 subjects (10%) did not complete at least 2 cycles of treatment and were not evaluated for disease response. The PFS-6 was 14% (4/28) [90% CI: 3%, 25%] with a median PFS time of 1.8 months [90%CI: 1.8, 1.9], a mean PFS time of 2.6 months [range 0.8 -11.9], a median overall survival of 9.9 months [90%CI: 8.3, 11.6] and a mean overall survival of 6.7 months [range 1.1 -15.9]. Best overall response by Macdonald criteria was partial response (n=3; 10%) and stable disease (n=7; 23%). Median duration of stable disease was 3.9 months [90% CI: 3.8, 4.0].
Conclusions: Single agent verubulin, in this dose and schedule, in adults with recurrent GBM is well tolerated and associated with acceptable toxicity, and appears to have modest activity.
Saturday June 4th. Poster Presentation Abstract 10529
"Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules."
Baichwal et al.
Background: MPC‑9528 is a potent, selective, orally bioavailable inhibitor of nicotinamide phosphoribosyltransferase (Nampt) that catalyzes the rate-limiting step in NAD biosynthesis from nicotinamide. Nampt inhibition results in NAD depletion, inhibition of ATP synthesis and cell death. MPC-9528 has potent tumoricidal activity against cancer cell lines of diverse origin and induces regressions in xenograft models. Here we explore determinants of MPC-9528 activity in xenografts by comparing tumor NAD depletion and survival with alternate dosing schedules. Methods: HT1080 human fibrosarcoma cells were implanted subcutaneously into athymic mice (nu/nu) for xenograft studies. MPC-9528 was dosed orally, once weekly or once or twice daily, for two or three weeks. NAD concentration in xenografts and mouse organs was determined by LC-MS/MS.
Results: MPC-9528 (75 mg/kg) dosed weekly for three weeks resulted in 75% xenograft regression 8 days after the last dose. ED50 with this schedule was 44 mg/kg and doses at or below 35 mg/kg showed no activity. All doses were well-tolerated with <10% change in median body weight. A dose of 10 mg/kg once daily, 3 mg/kg twice daily or 4 mg/kg twice daily for 14 days resulted in 91%, 92% and 100% tumor regression, respectively, by the end of dosing. Two of 10 animals in the 10 mg/kg and 3 mg/kg groups, and 9 in the 4 mg/kg group had no detectable tumors at the end of dosing. In the 10, 3 and 4 mg/kg groups, 40%, 50% and 70% of the mice, respectively, were tumor free thirty-four days after the last dose. Pharmacokinetic profiles of a 3, 10 or 75 mg/kg dose of MPC-9528 indicated that anti-tumor activity was not dependent on maximal plasma concentration or total absorbed dose but on maintenance of compound concentration above a specific efficacious concentration threshold. MPC-9528 also caused a rapid and sustained reduction of NAD in tumors with the magnitude and kinetics of NAD change dependent on the dose and schedule.
Conclusions: MPC-9528 induces regression of xenografts when its plasma concentration is maintained above a threshold efficacious concentration. It shows comparable activity when given intermittently, once weekly, or continuously on a once or twice daily schedule.
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