An Ongoing Phase 1/2a Study of ABT-263; Pharmacokinetics (PK), Safety and Anti-Tumor Activity in Patients (pts) with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).

Abstract 883

ABT-263, a novel orally bioavailable BH3 mimetic, binds with high affinity (K_i ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. In vitro, ABT-263 potently induces apoptosis (EC₅₀ ≤ 1μM) in Bcl-2 overexpressing human lymphoma cell lines and primary CLL cells. Preclinical mechanism-based toxicities include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, reflecting inhibition of Bcl-w, Bcl-2 and Bcl-X_L, respectively. Study M06-873 is a phase 1/2a dose-escalation trial employing a continuous reassessment method (CRM) to evaluate ABT-263 PK, safety and antitumor activity of two dosing schedules in pts with relapsed or refractory CLL. Tumor responses were evaluated by the NCI-WG criteria. Pts were initially dosed on d1-14 of a 21d cycle with 10-250 mg ABT-263. To ameliorate the impact of thrombocytopenia (TCP) due to on-target Bcl-X_L inhibition-induced platelet apoptosis, a 100 mg lead-in dose for 7d followed by continuous 21/21d dosing (up to 300mg/d) was investigated. This study has completed enrollment at 300 mg with 29 pts (15 on a 14/21d; 14 on a 21/21d schedule) as of June 2009. The PK exposure of ABT-263 was approximately dose-proportional from 10-300 mg with a terminal half-life of 11 h. Platelet nadirs were transient, occurring on d3-5 followed by partial recovery due to compensatory increased megakaryopoiesis during continued dosing. Lead-in dosing reduced the early platelet nadir, and minimized fluctuations in platelet count observed with intermittent dosing. Circulating platelet count dropped maximally during cycle 1 by an average 12%, 57%, 68% and 70% from baseline at 10 mg, 110 mg, 200 and 250 mg for the 14/21d schedule, and an average of 52%, 63%, 63% and 68% from baseline at 125 mg, 200 mg, 250 mg and 300 mg for the 21/21d schedule. Of the 21 evaluable pts, 2 had radiographically confirmed partial responses (99% and 79% reductions) and 3 had as yet unconfirmed nodal regression (100%, 71% and 55%). 7 pts maintained a ≥50% decrease in circulating absolute lymphocyte count for ≥ 2 months with 2 pts having PR by physical examination; the overall response rate was 33%. Stable disease was noted in 8 pts and 2 pts had progressive disease. Responses tend to be durable, with the median PFS not yet reached while the median time on study is 9 mos (range 0.63 - 18.4 mos). The most common adverse events (AE) were diarrhea (52%), nausea (44%), vomiting (24%), fatigue (24%) thrombocytopenia (TCP; 20%) and neutropenia (12%). Dose limiting toxicities (DLT) were observed in 3 pts on the 14/21d schedule; 2 at 110mg (hospitalization & Grade 4 TCP) and 1 at 250 mg (Grade 4 TCP). Among the 14 pts on the 21/21d schedule, 3 pts experienced DLT; 1 at 200 mg (Grade 4 TCP); 1 at 250 mg (Grade 2 nausea) and 1 at 300 mg (Grade 4 TCP). ABT-263 was well-tolerated and had favorable PK and acceptable safety profiles. One week 100mg/d lead-in followed by continuous dosing minimizes platelet nadir and cycle variability. Based on the 21/21d continuous dosing data, the CRM model projection for MTD converged. The recommended phase 2 dose is 100 mg 7-d lead-in followed by 250 mg/d continuous dosing.