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Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki<0.10 nM) than for BCL-XL (Ki=48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose-escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626.
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