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. In vitro, this novel class of drug (ABT-263 and ABT-737) potently induces apoptosis (EC50 ≤ 1μM) in Bcl-2 overexpressing human lymphoma cell-lines and primary CLL cells. On target toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, reflecting inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-873, a phase 1 dose-escalation study, is employing a continuous reassessment method to assess ABT-263 safety and anti-tumor activity of two dosing schedules in patients with relapsed or refractory CLL. Enrollment continues with 18 patients (15 on a 14/21 and 3 on a 21/21 dosing schedule) enrolled. Dose escalation of ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued to 250 mg. ABT-263 given on a 21/21 day dosing schedule continues at the 200 mg/day dose level following a one week lead-in dose of 100 mg/day. The pharmacokinetic profile of ABT-263 was linear from 10 – 250 mg. As expected with Bcl-xL inhibition, a dose-dependent reduction in circulating platelet counts was observed. Circulating platelet count dropped maximally by an average of 12%, 61%, 66%, and 70% from baseline at 10, 110, 200 and 250 mg, respectively. Typically, platelet nadirs were transient, occurring on days 3–5 followed by subsequent recovery during continued dosing, consistent with preclinical in vivo animal data demonstrating accelerated platelet apoptosis and compensatory increased production. With the 14 day on/7 day off schedule, DLT’s included one patient receiving 110 mg experienced events of tumor lysis (per laboratory values only) and grade 4 thrombocytopenia and 1 patient receiving 250 mg experienced an event of grade 4 thrombocytopenia. To date, the dose limiting toxicity (DLT) has not been defined for the continuous dosing schedule. For patients with bulky lymphadenopathy, a 92% reduction in the target lesion was noted in 1 subject dosed at 200 mg. Radiographic tumor reductions of less than 50% were observed in 2 additional subjects and there were 2 additional patients with stable disease without radiographic reductions. For subjects with lymphocytosis, 7 experienced ≥ 50% decreases in peripheral lymphocytes. At this time there are 10 active patients; 8 are off study as indicated: progressive disease (3), serious adverse events (3), withdrawal of consent (1) or other (1). ABT-263 is a novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor with predictable and manageable toxicity and anti-tumor activity in relapsed or refractory CLL patients. The thrombocytopenia is predictable and manageable. A one week lead-in dose of 100mg/day to minimize the depth of the initial platelet nadir, along with continuous dosing is now being explored.
Disclosures: Roberts:Abbott Laboratories: Research Funding. Brown:Abbott Laboratories: Consultancy; Celgene: Research Funding, Speakers Bureau; bayer: Honoraria, Research Funding. Kipps:Abbott laboratories: Consultancy, Research Funding; Celgene: Consultancy; Memgem, Amgen, Bayer, Biogen, Genmab, Genentech, Kinemed: Research Funding; Annual Tanaka Hematology series, Israeli Society of hematology: Honoraria; Biogen Idec: Consultancy. 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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