TY - JOUR
T1 - Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma
AU - Davids, Matthew S.
AU - Roberts, Andrew W.
AU - Seymour, John F.
AU - Pagel, John M.
AU - Kahl, Brad S.
AU - Wierda, William G.
AU - Puvvada, Soham
AU - Kipps, Thomas J.
AU - Anderson, Mary Ann
AU - Salem, Ahmed Hamed
AU - Dunbar, Martin
AU - Zhu, Ming
AU - Peale, Franklin
AU - Ross, Jeremy A.
AU - Gressick, Lori
AU - Desai, Monali
AU - Kim, Su Young
AU - Verdugo, Maria
AU - Humerickhouse, Rod A.
AU - Gordon, Gary B.
AU - Gerecitano, John F.
N1 - Funding Information:
Supported by AbbVie (which also funded editorial support) and Genentech; in part by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant No. P30 CA008748 (J.F.G.); and in part by a Career Development Award from the American Society of Clinical Oncology (M.S.D.).
Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2017/3/10
Y1 - 2017/3/10
N2 - 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. Treatmentemergent 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 ± 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.
AB - 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. Treatmentemergent 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 ± 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.
UR - http://www.scopus.com/inward/record.url?scp=85015799271&partnerID=8YFLogxK
U2 - 10.1200/JCO.2016.70.4320
DO - 10.1200/JCO.2016.70.4320
M3 - Article
C2 - 28095146
AN - SCOPUS:85015799271
SN - 0732-183X
VL - 35
SP - 826
EP - 833
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -