Preliminary Results of a Phase 1b Study (GP28331) Combining GDC-0199 (ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Abstract

IntroductionDespite progress in chronic lymphocytic leukemia (CLL) treatment, new therapies are needed especially for relapsed/refractory (R/R) patients (pts). BCL2 is an anti-apoptotic protein expressed at high levels in all cases of CLL. GDC-0199 is an oral, highly selective BCL2 inhibitor. Clinical data for GDC-0199 have shown promising anti-CLL activity. Obinutuzumab (Gazyva®, Gazyvaro™) is a Type II, glycoengineered anti-CD20 antibody that has increased direct cell death, and enhanced antibody-dependent cell-mediated cytotoxicity. Obinutuzumab and chlorambucil have demonstrated improved progression-free survival compared to rituximab and chlorambucil in previously untreated pts with CLL. Also, preclinical data suggest that GDC-0199 combined with obinutuzumab may show synergistic activity in CLL. Collectively, these data support combining GDC-0199 and obinutuzumab for pts with CLL. We present data from an ongoing phase 1b study that is evaluating the safety and tolerability of GDC-0199 in combination with obinutuzumab in R/R or previously untreated pts with CLL.MethodsPts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are enrolled in a 3+3 study design with cohorts ranging from 100 to 600 mg/day of GDC-0199. Study eligibility is not restricted by cytogenetics or CLL risk profile. Study drug administration incorporates a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS), and staggering of the two agents. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or obinutuzumab (Schedule B) introduced first. After completing combination therapy, R/R pts continue single-agent GDC-0199 until disease progression. Adverse events (AEs) are graded according to NCI-CTCAE v.4 criteria. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination treatment and focus on potential AEs of TLS, infusion related reactions (IRRs), and cytopenias. [Display omitted] ResultsAs of May 2014, 9 R/R pts are on the dose finding stage of the study; 4 additional R/R pts were enrolled and discontinued following clinical TLS events in other GDC-0199 studies. No clinical TLS was observed in these 4 pts. The data presented here describe the 9 pts who continue on study treatment. Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 0 pts, medium risk 4 pts, and high risk 5 pts. Median time on study was 98 (range 7-252) days. No DLTs were observed in the 3 pts enrolled in the 100 mg GDC-0199 dosing cohort. Six pts were enrolled in the 200 mg GDC-0199 dosing cohort due to expansion following a DLT of laboratory TLS (characterized by asymptomatic laboratory abnormalities in potassium and phosphate) observed in 1 of the first 3 pts. Baseline characteristics include: median age 69 (range 59-80) years, 6 male pts, median of 4 prior CLL therapies (range 1-6), beta-2 microglobulin of ≥3.5 mg/L in 7 of 8 pts with available data, and IGVH mutation in 1 of 7 pts with available data. Cytogenetic data are available for 4 pts: none had del17p, 1 pt had del 11q, 1 pt had trisomy 12 and 2 pts had del 13q. The most common AEs included neutropenia (Figure 2). Dose interruptions of GDC-0199 or obinutuzumab in response to AEs were observed in 5 pts (2 pts had dose interruptions for obinutuzumab only [IRRs], and 3 pts had dose interruptions for GDC-0199 [mainly electrolyte abnormalities and cytopenias] and obinutuzumab [IRRs]); 1 pt in the 100 mg GDC-0199 dosing cohort had a dose reduction to 50 mg per day after 2 cycles of combination therapy due to ongoing neutropenia, and subsequently completed 6 cycles of combination treatment. IRRs were limited to the first infusion of obinutuzumab and were of Grade ≤2. One event of Grade 3 pneumonia required hospitalization. No treatment emergent bleeding events or deaths occurred on study.<![if !vml]><![endif]> [Display omitted] ConclusionThis is the first study combining GDC-0199 and the novel anti-CD20 antibody obinutuzumab in CLL and suggests that the combination is safely administered at the doses given. Prophylactic measures and a gradual dose ramp-up of GDC-0199 appear to reduce the incidence of TLS. Despite 9 pts being identified as medium or high risk for TLS, only 1 developed laboratory TLS, which was transient and managed. No clinical TLS was observed in these 9 pts. Dose escalation continues in R/R pts at 400 mg/day of GDC-0199. Schedule B and previously untreated pts will be enrolled in the near future. DisclosuresFlinn:Genentech: Research Funding. Brunvand:Genentech: Speakers Bureau. Hillman:Roche Pharmaceuticals: Honoraria, Research Funding. Jones:Genentech: Advisory Board Other. Lymp:Genentech: Employment. Elhamy:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Kipps:Cegene, Pharacyclics, AbbVie, Genentech: Advisory Board Other, Research Funding.