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J Clin Oncol. 2017 Mar 10;35(8):826-833. doi: 10.1200/JCO.2016.70.4320. Epub 2017 Jan 17.

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.

Author information

1
Matthew S. Davids, Dana-Farber Cancer Institute, Boston, MA; Andrew W. Roberts, John F. Seymour, and Mary Ann Anderson, University of Melbourne; Andrew W. Roberts and Mary Ann Anderson, Royal Melbourne Hospital and Eliza Hall Institute of Medical Research; and John F. Seymour, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; John M. Pagel, Swedish Cancer Institute, Seattle, WA; Brad S. Kahl, Washington University Medical School, St Louis, MO; William G. Wierda, University of Texas MD Anderson Cancer Center, Houston, TX; Soham Puvvada, University of Arizona, Tucson, AZ; Thomas J. Kipps, University of California San Diego, San Diego, CA; Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Jeremy A. Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A. Humerickhouse, and Gary B. Gordon, AbbVie, Chicago, IL; Ahmed Hamed Salem, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Franklin Peale, Genentech, South San Francisco, CA; John F. Gerecitano, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY.

Abstract

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

PMID:
28095146
PMCID:
PMC5455685
DOI:
10.1200/JCO.2016.70.4320
[Indexed for MEDLINE]
Free PMC Article

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