Session: 636. Myelodysplastic Syndromes—Basic and Translational Studies: Poster III
Hematology Disease Topics & Pathways:
apoptosis, Therapies, Non-Biological, chemical interactions, Biological Processes, epigenetics
Cell viability and induction of apoptosis was assessed following treatment with alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of alvocidib administration with HMAs, were performed. Treatment of AML cell lines with alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating alvocidib activity compared to azacytidine.
These non-clinical data suggest that an alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency.
Disclosures: Kim: Tolero Pharmaceuticals, Inc: Employment. Whatcott: Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain: Tolero Pharmaceuticals, Inc: Employment. Anthony: Tolero Pharmaceuticals, Inc: Employment. Bearss: Tolero Pharmaceuticals, Inc: Employment. Warner: Tolero Pharmaceuticals: Employment.
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