Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and Bcl-2 inhibitor venetoclax have demonstrated significant clinical activity in CLL and based on complementary mechanisms are ideal for combination. However, combining venetoclax with other active agents raises safety concerns as it may increase the risk of 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 three dose levels of venetoclax and identified the FDA approved doses of all three agents 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% CI: 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-na?ve patients as well as larger phase 3 trials currently in planning. The study is registered to https://clinicaltrials.gov asNCT02427451.
