Reduction in platelet counts as a mechanistic biomarker and guide for adaptive dose-escalation in phase I studies of the Bcl-2 family inhibitor ABT-263

Abstract

3542 Background: ABT-263 is a novel, BH3 mimetic that binds with high affinity (Ki 1 nanoM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based toxicity (EC50 1 microM) against human cell lines derived from lymphoid and small cell lung cancers (SCLC). Mechanistic toxicities observed pre-clinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased circulating platelet survival, presumably mediated by Bcl-w, Bcl-2 and Bcl-XL, respectively. Methods: Three enrolling Phase 1 dose-escalation studies are using either a modified Fibonnaci 3 + 3 design (M06–814: lymphoid malignancies) or a continuous reassessment method (CRM; M06–822: SCLC/solid tumors and M06–873: CLL). The CRM uses dose limiting toxicity (DLT) data to estimate MTD and guide dose escalation. ABT-263 was dosed for 14 days with a 7-day rest period. Results: Fifty-four subjects enrolled in the 3 studies at doses ranging from 10 mg to 315 mg. ABT-263 exposure was dose-proportional with plasma levels above the preclinical efficacy threshold achieved at 315 mg. The average half-life was 14 to 20 hours. Three DLTs were observed, one grade 3 URI at 160 mg, one grade 3 ALT elevation at 315 mg and one fatal respiratory failure at 10 mg in a SCLC patient. Dose- related thrombocytopenia consistent with preclinical models was observed. At 315 mg mean platelet reduction of 69% was observed. Typically, platelet nadir occurred on days 3 to 5 with recovery during continued dosing. This pattern is consistent with preclinical evidence of accelerated platelet senescence and compensatory increased production. Tumor regression was observed in 6 patients with CLL/SLL, NK/T cell or follicular lymphoma, with 3 patients showing > 50% tumor shrinkage. Conclusions: ABT-263 induces a transient decrease in circulating platelets via inhibition of Bcl-XL, without decreasing platelet production. This transient reduction in platelets is manageable, predictable and confirms on target activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories