Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia

Abstract

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

Conflict of interest statement

Conflict-of-interest disclosure: K.A.R. receives research funding from Genentech. F.T.A. has consulted for AbbVie, Gilead Sciences, and Janssen and receives research funding from Pharmacyclics. G.L. receives research funding from Genentech. K.J.M. has received research funding from Pharmacyclics, Novartis, Merck, and BMS and has consulted for Pharmacyclics, Janssen, Genentech, BMS, and Acerta. J.A.W. received honoraria from Janssen, has consulted for Janssen, and receives research funding from MorphoSys, Karyopharm Therapeutics, and AbbVie. J.A.J. is employed by Celgene Corporation and has consulted for Genentech, Roche, AbbVie, and Pharmacyclics. J.C.B. receives research funding from Genentech, Acerta, Pharmacyclics, and Janssen. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment responses with minimal residual disease status. MRD was assessed by 10-color flow cytometry at both planned response assessments: midtherapy after cycle 8 (A) and end of treatment 2 months after completion of cycle 14 (B). The limit of detection for MRD is less than 1 × 10−4. BM, bone marrow; PB, peripheral blood.