Abstract
Abstract 1711
Poster Board I-737
Bcl-2 family members are associated with tumor initiation and drug resistance, and are compelling therapeutic targets. ABT-263 is a novel, orally bioavailable, small molecule inhibitor of antiapoptotic Bcl-2 family proteins that binds with high affinity (Ki '1 nM) to Bcl-2, Bcl-xL, and Bcl-w. ABT-263 displays potent preclinical mechanism-based targeted cytotoxicity (EC50 '1 μM) against human tumor cell lines (small cell lung carcinomas and T and B lymphoid malignancies) that over express Bcl-2. Toxicities are mechanism-based, with Bcl-2, Bcl-xL and Bcl-w mediating effects on lymphocytes, platelet survival and testicular toxicity, respectively. The objective of this study was to assess safety/pharmacokinetics (PK) and maximum tolerated dose of ABT-263. Study M06-814 is a phase 1/2a, dose-escalation, single-agent international study employing a modified Fibonacci 3+3 of ABT-263 in relapsed/refractory lymphoid malignancies. Patients (pts) were dosed on Days (d) 1-14 of a 21-d dosing cycle with 10-440 mg ABT-263, or continuous 21/21-d dosing (21-d cycle) with 200-325 mg ABT-263 following a 150 mg lead-in dose. Tumor responses were evaluated using the IWG criteria. To date, 50 pts (38 on a 14/21-d and 12 on a 21/21-d dosing schedule) have been dosed with ABT-263. The median pts age is 59 y [range, 20-81]).The PK profile of ABT-263 on the 14/21-d schedule was linear and dose proportional from 10-440 mg with a t½ of 14-20 h. Platelet nadirs were transient, occurring on d 3-5, and preliminary data suggests a 1-week low dose lead-in at 150 mg ABT-263 followed by a 21/21-d dosing schedule minimizes platelet nadir and cycle variability. The median progression-free survival is 88 d [95% CI: 46, 170]. Of the 50 pts enrolled, 1 NK-T cell lymphoma had a 75% reduction in cutaneous lesions, 1 follicular lymphoma had an unconfirmed partial response (PR) and 7 CLL pts had PR's due to decreases in lymphadenopathy with 7 other achieving at least a 50% decrease in circulating lymphocytes. 4 pts on the 14/21-d schedule had dose-limiting toxicities (DLT); 1 at 160 mg (bronchitis), 2 at 315 mg (elevated ALT and Grade 4 Thrombocytopenia [TCP]) and 1 at 440 mg (worsening pleural effusion in a pt with underlying afib and hypotension). Among the 12 pts on the 21/21-d schedule, 1 experienced DLT at 275 mg (Grade 4 TCP). Overall, TCP was predictable and manageable. Of the 3 pts who had discontinued therapy at the time of this analysis, 2 discontinued due to PD and 1 withdrew consent. ABT-263 is well tolerated with a linear PK, toxicity secondary to on-target activity and antitumor activity in pts with relapsed or refractory lymphoid malignancies. Toxicities were predictable and manageable; identification of optimal dose and schedule for phase 1 trials continues.
Off Label Use: ABT-263 is an experimental drug that is not yet registered. It is designed to induce apoptosis in tumor cells.. O'Connor:Abbott: Research Funding. Czuczman:Abbott and Genentech: Consultancy. Tulpule:Abbott: Research Funding. Xiong:Abbott: Employment. Chiu:Abbott: Employment. Busman:Abbott: Employment. Enschede:Abbott: Employment. Krivoshik:Abbott: Employment. Humerickhouse:Abbott: Employment.
Author notes
Asterisk with author names denotes non-ASH members.
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