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).

Leukemia Myelodysplasia and Transplantation
Session Type and Session Title: 
Poster Discussion Session, Leukemia, Myelodysplasia, and Transplantation
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 7018)
John Francis Seymour, Matthew Steven Davids, John M. Pagel, Brad S. Kahl, William G. Wierda, Thomas P. Miller, John F. Gerecitano, Thomas J. Kipps, Mary Ann Anderson, David C.S. Huang, David E. Darden, Lori A. Gressick, Cathy E. Nolan, Jianning Yang, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew Warwick Roberts; Peter MacCallum Cancer Center, Melbourne, Australia; Dana-Farber Cancer Institute, Boston, MA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Wisconsin Carbone Cancer Center, Madison, WI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Arizona Cancer Center, Tucson, AZ; Memorial Sloan-Kettering Cancer Center, New York, NY; UC San Diego Moores Cancer Center, La Jolla, CA; Royal Melbourne Hospital; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; AbbVie, Inc, North Chicago, IL; Royal Melbourne Hospital, Melbourne, Australia

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Abstract Disclosures


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.