The PARP Inhibitor Veliparib Can Be Safely Added to Bendamustine and Rituximab and Has Preliminary Evidence of Activity in B-Cell Lymphoma

• Published in: Clinical cancer research 2017-08, Vol.23 (15), p.4119-4126
• Main Authors: Soumerai, Jacob D, Zelenetz, Andrew D, Moskowitz, Craig H, Palomba, M Lia, Hamlin, Jr, Paul A, Noy, Ariela, Straus, David J, Moskowitz, Alison J, Younes, Anas, Matasar, Matthew J, Horwitz, Steven M, Portlock, Carol S, Konner, Jason A, Gounder, Mrinal M, Hyman, David M, Voss, Martin H, Fury, Matthew G, Gajria, Devika, Carvajal, Richard D, Ho, Alan L, Beumer, Jan H, Kiesel, Brian, Zhang, Zhigang, Chen, Alice, Little, Richard F, Jarjies, Christine, Dang, Thu O, France, Fallon, Mishra, Nishant, Gerecitano, John F
• Format: Article
• Language: English
• Subjects: Alkylating agents; Alkylation; Anemia; B-cell lymphoma; Cancer; Cytotoxicity; Expansion; Experimental design; Hypertension; Hypophosphatemia; Immunotherapy; Inhibitors; Leukopenia; Lymphocytes B; Lymphoma; Lymphopenia; Monoclonal antibodies; Multiple myeloma; Nausea; Neutropenia; Patients; Pharmacokinetics; Pharmacology; Poly(ADP-ribose) polymerase; Quality; Rituximab; Targeted cancer therapy; Thrombocytopenia; Toxicity
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3068

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. 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/m intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m , 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. The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m Dose-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. 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 NCT01326702 .