Bcl-2 Inhibitor ABT-199 (GDC-0199) Monotherapy Shows Anti-Tumor Activity Including Complete Remissions In High-Risk Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Novel agents are needed for CLL/SLL patients (pts) R/R to standard therapies. The intrinsic apoptotic pathway is often dysregulated in relapsed CLL/SLL due to a deficiency in pro-apoptotic proteins such as TP53 and overexpression of anti-apoptotic proteins such as Bcl-2. ABT-199 is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor that can trigger apoptosis in vitro, even in del(17p) CLL cells, making it a promising agent for the treatment of pts with CLL/SLL.

The primary objectives of this phase I, dose-escalation study were to evaluate the safety, pharmacokinetics (PK), determine a maximum tolerated dose, and a recommended phase 2 dose of ABT-199. Secondary objectives were to assess efficacy and to explore biomarkers for response. Pts received a single dose of ABT-199 on Week1 Day -3 or -7 (W1D-3, W1D-7), followed by continuous once-daily dosing from W1D1, until disease progression or unacceptable toxicity. Modifications were made to the dose escalation scheme and tumor lysis syndrome (TLS) prophylaxis and monitoring schedule after TLS was observed in some pts. Evaluations included adverse events (AE; NCI-CTCAE-V4), Cairo-Bishop definitions of laboratory and clinical TLS, PK parameters and response.

As of July 4, 2013, 56 pts were enrolled in cohorts at doses from 150 to 1200 mg, with a median time on study of 10.0 months (range 0-21.0). 17 (38%) pts had del(17p) and 18 (32%) had fludarabine (F)-refractory disease. 12 of 27 (44%) pts had beta-2 microglobulin levels >3 mg/L and 20 of 24 (83%) had IGVH unmutated status. 22 pts discontinued (D/C) ABT-199: 8 due to AEs, 12 due to progressive disease, 2 for other reasons (1 had a pulmonary embolus requiring Coumadin and 1 went to transplant in response). The most common AEs (All grades, ≥25% pts) were diarrhea (46%), neutropenia (43%), fatigue (34%), upper respiratory tract infection (29%), and cough (25%). Grade (G) 3/4 AEs occurring in ≥4 pts were neutropenia (41%), TLS (11%), thrombocytopenia (10%), hyperglycemia (10%), anemia (7%), and febrile neutropenia (7%). 7 DLTs have occurred to date: 5 TLS (1 G3 laboratory at 50 mg; 1 G4 clinical at 50 mg; 1 G3 laboratory at 100 mg and 2 at 200 mg); 1 G4 neutropenia (600 mg); and sudden death (1200 mg) in the setting of G4 (clinical) TLS. After a single dose of ABT-199 with food, T_max and T_1/2 values were approximately 6 and 17 hrs, respectively, supporting daily dosing. Preliminary efficacy data are summarized in the table below. In pts achieving CR/CRi, minimal residual disease (MRD) was quantified with 4 color flow cytometry using local lab methods (aiming to analyze >200,000 nucleated cells) and interpretation. 8 pts have evaluable results with no detectable MRD in 4 (2 with suboptimal cells analyzed) and low level MRD was found in 4 (0.05, 0.7, 0.75%; quantification pending in 1). Of the pts who had no detectable MRD, 1 pt was F-refractory and del(17p) and 2 pts were F-refractory.

ABT-199 showed activity in pts with R/R CLL with a response rate of 84% for the study population, including 20% CR/CRi. Pts with high-risk CLL showed similar efficacy with a response rate of 82% in del(17p) and 78% in F-refractory disease. Notably, 3 of the 4 pts who had no detectable MRD and achieved a CR/CRi were high-risk disease pts. This study is continuing enrollment using a revised dosing schedule designed to reduce the identified risk of TLS. A phase 2 monotherapy study in pts with relapsed del(17p) CLL has commenced as well as combination studies with either rituximab or obinutuzumab in pts with relapsed CLL.

SeymourGenentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Kahl:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding. Wierda:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau. Gerecitano:AbbVie: Research Funding; Genentech: Research Funding. Kipps:AbbVie, Inc.: Consultancy, Research Funding. Anderson:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, which recieves commercial income related to ABT-199, Employee, which recieves commercial income related to ABT-199 Other. Huang:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment. Rudersdorf:AbbVie, Inc.: Employment, Stock Other. Gressick:AbbVie, Inc: Employment, Stock Other. Montalvo:AbbVie, Inc.: Employment, Stock Other. Yang:AbbVie, Inc.: Employment, Stock Other. Busman:AbbVie, Inc.: Employment, Stock Other. Dunbar:AbbVie, Inc.: Employment, Stock Other. Cerri:AbbVie, Inc.: Employment, Stock Other. Enschede:AbbVie, Inc.: Employment, Stock Other. Humerickhouse:AbbVie, Inc.: Employment, Stock Other. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment.