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

被引：599

作者：

Davids, Matthew S. ^{[1
]}

Roberts, Andrew W. ^{[2
,3
,4
]}

Seymour, John F. ^{[2
,5
]}

Pagel, John M. ^{[6
]}

Kahl, Brad S. ^{[7
]}

Wierda, William G. ^{[8
]}

Puvvada, Soham ^{[9
]}

Kipps, Thomas J. ^{[10
]}

Anderson, Mary Ann ^{[2
,3
,4
]}

Salem, Ahmed Hamed ^{[11
,12
]}

Dunbar, Martin ^{[11
]}

Zhu, Ming ^{[11
]}

Peale, Franklin ^{[13
]}

Ross, Jeremy A. ^{[11
]}

Gressick, Lori ^{[11
]}

Desai, Monali ^{[11
]}

Kim, Su Young ^{[11
]}

Verdugo, Maria ^{[11
]}

Humerickhouse, Rod A. ^{[11
]}

Gordon, Gary B. ^{[11
]}

Gerecitano, John F. ^{[14
,15
]}

机构：

[1] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA

[2] Univ Melbourne, Melbourne, Vic, Australia

[3] Royal Melbourne Hosp, Melbourne, Vic, Australia

[4] Eliza Hall Inst Med Res, Melbourne, Vic, Australia

[5] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[6] Swedish Canc Inst, Seattle, WA USA

[7] Washington Univ, Sch Med, St Louis, MO USA

[8] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[9] Univ Arizona, Tucson, AZ USA

[10] Univ Calif San Diego, San Diego, CA 92103 USA

[11] AbbVie, Chicago, IL USA

[12] Ain Shams Univ, Fac Pharm, Cairo, Egypt

[13] Genentech Inc, San Francisco, CA 94080 USA

[14] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[15] Weill Cornell Med Ctr, New York, NY USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2017年 / 35卷 / 08期

基金：

美国国家卫生研究院;

关键词：

B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR LYSIS SYNDROME; ANTITUMOR-ACTIVITY; CHROMOSOME-TRANSLOCATION; SELECTIVE INHIBITOR; DOSE-ESCALATION; GENE-EXPRESSION; BCL2; PHARMACOKINETICS;

D O I：

10.1200/JCO.2016.70.4320

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2017 by American Society of Clinical Oncology

引用

页码：826 / 833

页数：8

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