Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma.
Purpose:Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design:Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results:Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions:The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.
Stanford University Medical Center, Stanford, California. radvani@stanford.edu.
Ranjana H
RH
Advani
University of Michigan Medical School, Ann Arbor, Michigan.
Daniel
D
Lebovic
Oregon Health and Science University, Portland, Oregon.
Andy
A
Chen
Rocky Mountain Cancer Center, Denver, Colorado.
Mark
M
Brunvand
Hackensack University Medical Center, Hackensack, New Jersey.
Andre
A
Goy
University of Wisconsin-Madison, Madison, Wisconsin.
Julie E
JE
Chang
Massachusetts General Hospital, Boston, Massachusetts.
Ephraim
E
Hochberg
Genentech, Inc., South San Francisco, California.
Sreeni
S
Yalamanchili
Genentech, Inc., South San Francisco, California.
Robert
R
Kahn
Genentech, Inc., South San Francisco, California.
Dan
D
Lu
Genentech, Inc., South San Francisco, California.
Priya
P
Agarwal
Genentech, Inc., South San Francisco, California.
Randall C
RC
Dere
Genentech, Inc., South San Francisco, California.
Hsin-Ju
HJ
Hsieh
Genentech, Inc., South San Francisco, California.
Surai
S
Jones
Genentech, Inc., South San Francisco, California.
Yu-Waye
YW
Chu
Georgetown University Hospital, Washington, D.C.
Bruce D
BD
Cheson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D062365:Aminobenzoates / Q000008:administration & dosage; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage; D000069283:Rituximab / Q000008:administration & dosage* / Q000009:adverse effects; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology
D062365:Aminobenzoates; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D009842:Oligopeptides; D051918:Sialic Acid Binding Ig-like Lectin 2; C543533:auristatin; D000069283:Rituximab; C000603979:pinatuzumab vedotin