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

Kristeleit, R; Shapiro, GI; Burris, HA; Oza, AM; LoRusso, P; Patel, MR; Domchek, SM; ... Shapira-Frommer, R; + view all (2017) A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clinical Cancer Research , 23 (15) pp. 4095-4106. 10.1158/1078-0432.CCR-16-2796. Green open access

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Abstract

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. Clin Cancer Res; 23(15); 4095–106. ©2017 AACR. This article is featured in Highlights of This Issue, p. 3975 Translational Relevance PARP-1, PARP-2, and PARP-3 enzymes are key mediators of DNA repair in response to single-strand breaks. Inhibition of these enzymes results in accumulation of double-strand DNA breaks that are repaired through BRCA1- and BRCA2-mediated homologous recombination (HR). Defects in HR repair (e.g., BRCA1 and BRCA2 mutations) can sensitize tumors to PARP inhibition through synthetic lethality. This phase I–II study was the first to fully evaluate single-agent oral rucaparib, a PARP inhibitor, in heavily pretreated patients with advanced solid tumors. In part 1, pharmacokinetics were dose proportional, safety was manageable, and rucaparib 600 mg twice daily was the recommended phase II dose. In part 2A, rucaparib 600 mg twice-daily treatment had robust antitumor activity in patients with platinum-sensitive ovarian cancer and a germline BRCA1/2 mutation. These results support further clinical and translational investigation of rucaparib in tumors with HR repair deficiency, potentially extending applicability beyond BRCA-mutated cancers.

Type: Article
Title: A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-16-2796
Publisher version: https://doi.org/10.1158/1078-0432.CCR-16-2796
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, POLY(ADP-RIBOSE) POLYMERASE INHIBITOR, BRCA MUTATION CARRIERS, STRAND BREAK REPAIR, DNA-REPAIR, FALLOPIAN-TUBE, OPEN-LABEL, EPITHELIAL OVARIAN, PRIMARY PERITONEAL, DOSE-ESCALATION, HUMAN CANCERS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1544874
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