The PARP Inhibitor Veliparib Can Be Safely Added to Bendamustine and Rituximab and Has Preliminary Evidence of Activity in B-Cell Lymphoma.
Purpose:The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design:This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20-400 mg twice a day, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results:The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions:VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702Clin Cancer Res; 23(15); 4119-26. ©2017 AACR.
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York. soumeraj@mskcc.org.
Jacob D
JD
Soumerai
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Andrew D
AD
Zelenetz
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Craig H
CH
Moskowitz
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
M Lia
ML
Palomba
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Paul A
PA
Hamlin
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Ariela
A
Noy
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
David J
DJ
Straus
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Alison J
AJ
Moskowitz
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Anas
A
Younes
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Matthew J
MJ
Matasar
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Steven M
SM
Horwitz
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Carol S
CS
Portlock
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Jason A
JA
Konner
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Mrinal M
MM
Gounder
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
David M
DM
Hyman
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Martin H
MH
Voss
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Matthew G
MG
Fury
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Devika
D
Gajria
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Richard D
RD
Carvajal
Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
Alan L
AL
Ho
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.|Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Jan H
JH
Beumer
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Brian
B
Kiesel
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Zhigang
Z
Zhang
Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland.
Alice
A
Chen
Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland.
Richard F
RF
Little
Memorial Sloan Kettering Cancer Center, New York, New York.
Christine
C
Jarjies
Memorial Sloan Kettering Cancer Center, New York, New York.
Thu O
TO
Dang
Memorial Sloan Kettering Cancer Center, New York, New York.
Fallon
F
France
Memorial Sloan Kettering Cancer Center, New York, New York.
Nishant
N
Mishra
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Center for Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York.
John F
JF
Gerecitano
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000069283:Rituximab / Q000008:administration & dosage* / Q000009:adverse effects
D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride