Abstract

ABT-263 is a novel, orally bioavailable BH3 mimetic that binds with high affinity (Ki ≤1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based activity (EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell-lines. Mechanistic toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, presumably mediated by inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-814, a phase 1 dose-escalation study is employing a modified Fibonaci 3 + 3 design to assess ABT-263 safety, pharmacokinetics and anti-tumor activity of two dosing schedules in patients with relapsed or refractory lymphoid malignancies. Enrollment continues with 42 patients (39 on a 14/21 day and 3 on a 21/21 day dosing schedule) enrolled. ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued escalation to 440 mg, with 315 mg defined as tolerable. The pharmacokinetic profile of ABT-263 on the 14/21 day schedule was linear from 10 – 440 mg with a t1/2 of 14 – 20 h. Consistent with preclinical models, a dose-dependent reduction in circulating platelets was observed. Typically, platelet nadirs were transient, occurring on days 3–5 with subsequent recovery during continued dosing, consistent with accelerated platelet apoptosis and compensatory increased bone marrow release and production. Thrombocytopenia was predictable and manageable. A one week lead-in dosing period at 150mg ABT-263 and a 21/21 day dosing schedule beginning at 200 mg, are being evaluated as measures to ameliorate the platelet nadir. Dose limiting toxicities on cycle 1 in the 14/21 day dosing schedule occurred at 160 mg (bronchitis), 315 mg (elevated ALT and gr 4 thrombocytopenia), and 440 mg (dyspnea). Responses were observed in 3 patients including a 75% and 99% reduction of bulky masses in 2 CLL/SLL and a 75% reduction in a NK/T cell lymphoma. Minor nodal responses occurred in 4 patients with follicular lymphoma and 3 patients with CLL/SLL. Additionally, 2 patients with CLL/SLL had ≥50% decreases in leukemic cells for at least 2 months. ABT-263 is a well tolerated oral small molecular inhibitor of Bcl-2 family proteins with a linear PK, toxicity profile indicative of on-target activity and anti-tumor activity in patients with relapsed or refractory lymphoid malignancies. Accrual continues.

Disclosures: Wilson:Abbott Laboratories: Research Funding. O’Connor:Abbott Laboratories: Research Funding. Czuczman:Abbott Laboratories and Genentech: Consultancy. Tulpule:Abbott Laboratories: Research Funding. Xiong:Abbott Laboratories: Employment. Chiu:Abbott Laboratories: Employment. Busman:Abbott Laboratories: Employment. Knight:Abbott Laboratories: Employment. Enschede:Abbott Laboratories: Employment. Krivoshik:Abbott Laboratories: Employment. Humerickhouse:Abbott Laboratories: Employment.

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