@article{200ae777a3984835b582a6e2a632901f,
title = "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{\textquoteright}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.",
author = "Rogers, {Kerry A.} and Ying Huang and Ruppert, {Amy S.} and Awan, {Farrukh T.} and Heerema, {Nyla A.} and Corinne Hoffman and Gerard Lozanski and Maddocks, {Kami J.} and Moran, {Mollie E.} and Reid, {Mark A.} and Margaret Lucas and Woyach, {Jennifer A.} and {Thomas Whitlow}, W. and Jones, {Jeffrey A.} and Byrd, {John C.}",
note = "Funding Information: Leukemia and Lymphoma Society, Vysis Inc. (part of Abbott Molecular), and the National Institutes of Health, National Cancer Institute (R01 CA177292 and R35 CA197734 to J.C.B.). Research reported in this publication was supported in part by the Ohio State University Comprehensive Cancer Center and the National Institutes of Health, National Cancer Institute under grant number P30 CA016058. Funding Information: 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. Funding Information: The authors acknowledge Genentech for funding this study. Work in this trial supported in part by funding from the Four Winds Foundation, Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology.",
year = "2018",
month = oct,
day = "11",
doi = "10.1182/blood-2018-05-853564",
language = "English (US)",
volume = "132",
pages = "1568--1572",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",
}