A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

作者：Kristeleit, Rebecca^*; Shapiro, Geoffrey I.; Burris, Howard A.; Oza, Amit M.; LoRusso, Patricia; Patel, Manish R.; Domchek, Susan M.; Balmana, Judith; Drew, Yvette; Chen, Lee-may; Safra, Tamar; Montes, Ana; Giordano, Heidi; Maloney, Lara; Goble, Sandra; Isaacson, Jeff; Xiao, Jim; Borrow, Jen; Rolfe, Lindsey; Shapira-Frommer, Ronnie

来源：Clinical Cancer Research, 2017, 23(15): 4095-4106.

DOI：10.1158/1078-0432.CCR-16-2796

• POLY(ADP-RIBOSE) POLYMERASE INHIBITOR
• BRCA MUTATION CARRIERS
• FALLOPIAN-TUBE
• OPEN-LABEL
• EPITHELIAL OVARIAN
• PRIMARY PERITONEAL
• DOSE-ESCALATION
• HUMAN CANCERS
• REPAIR
• MULTICENTER

Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate single-agent oral rucaparib at multiple doses. @@@ Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1. @@@ Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression). @@@ Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC.

• 出版日期2017-8-1