Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma

Davids, MS; Roberts, AW; Seymour, JF; Pagel, JM; Kahl, BS; Wierda, WG; Puvvada, S; Kipps, TJ; Anderson, MA; Salem, AH; Dunbar, M; Zhu, M; Peale, F; Ross, JA; Gressick, L; Desai, M; Kim, SY; Verdugo, M; Humerickhouse, RA; Gordon, GB; Gerecitano, JF

Author(s): Davids, MS; Roberts, AW; Seymour, JF; Pagel, JM; Kahl, BS; Wierda, WG; Puvvada, S; Kipps, TJ; Anderson, MA; Salem, AH; Dunbar, M; Zhu, M; Peale, F; Ross, JA; Gressick, L; Desai, M; Kim, SY; Verdugo, M; Humerickhouse, RA; Gordon, GB; Gerecitano, JF;
Details: Publication Year 2017-03-10,Volume 35,Issue #8,Page 826-833
Journal Title: J Clin Oncol
Publication Type: Journal Article
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), Waldenstrom 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.
Research Division(s): Cancer And Haematology
PubMed ID: 28095146
Link To PubMed Central Version: https://www-ncbi.nlm.nih.gov/pmc/articles/PMC5455685/
Publisher's Version: https://doi.org/10.1200/JCO.2016.70.4320
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-06-26 02:15:24

Last Modified: 2018-03-14 09:13:01