Soumerai Jacob D, Zelenetz Andrew D, Moskowitz Craig H, Palomba M Lia, Hamlin 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
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.
Clin Cancer Res. 2017 Aug 1;23(15):4119-4126. doi: 10.1158/1078-0432.CCR-16-3068. Epub 2017 Mar 17.
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 .
聚（ADP-核糖）聚合酶（PARP）抑制剂维利帕尼可增强烷化剂的细胞毒性。这项I期研究评估了维利帕尼与双功能烷化剂苯达莫司汀（VB）联合用于复发/难治性淋巴瘤、多发性骨髓瘤和实体恶性肿瘤患者的情况，在B细胞淋巴瘤患者中对VB联合利妥昔单抗（VBR）进行了队列扩展。这项剂量递增研究评估了维利帕尼（28天周期的第1 - 7天，每日两次，20 - 400 mg）和苯达莫司汀（第1天和第2天，静脉注射70和90 mg/m²）的安全性、药代动力学和初步疗效。进行了队列扩展，在B细胞淋巴瘤患者中将维利帕尼和苯达莫司汀以最大耐受剂量（MTD）与利妥昔单抗（375 mg/m²，第1天）联合使用。七个剂量递增队列中有34名患者接受了治疗，剂量扩展队列中有7名患者接受了治疗。MTD为维利帕尼每日两次300 mg加苯达莫司汀90 mg/m²。剂量限制性毒性（DLT）为贫血、恶心、高血压和多汗。≥3级毒性包括淋巴细胞减少（87.8%）、贫血（19.5%）、中性粒细胞减少（12.2%）、血小板减少（9.8%）、白细胞减少（9.8%）、恶心（7.3%）和低磷血症（7.3%）。维利帕尼的表观清除率略低于先前报道。在14名可评估反应的淋巴瘤患者中，VB组7名患者中有5名（71%）、VBR组7名患者中有6名（86%）达到客观缓解。1名多发性骨髓瘤患者获得部分缓解。VB和VBR总体耐受性良好。VBR在B细胞淋巴瘤患者中具有初步临床活性，值得在II期试验中进一步研究。该试验已在www.clinicaltrials.gov注册，注册号为NCT01326702。
