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Clin Cancer Res. 2017 Aug 1;23(15):4095-4106. doi: 10.1158/1078-0432.CCR-16-2796. Epub 2017 Mar 6.

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

Author information

1
Research Department of Oncology, UCL Cancer Institute, London, United Kingdom. r.kristeleit@ucl.ac.uk.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Medical Oncology, Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, Tennessee.
4
Department of Obstetrics and Gynecology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
5
Department of Medical Oncology, Yale University, New Haven, Connecticut.
6
Department of Medical Oncology, Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, Florida.
7
Department of Medical Oncology, Basser Center for BRCA, University of Pennsylvania, Philadelphia, Pennsylvania.
8
Department of Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
9
Department of Medical Oncology, Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom.
10
Department of Obstetrics, Gynecology, and Reproductive Sciences, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
11
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
12
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
13
Department of Medical Oncology, Guy's Hospital, London, United Kingdom.
14
Clinical Science, Clovis Oncology, Inc., Boulder, Colorado.
15
Biostatistics, Clovis Oncology, Inc., Boulder, Colorado.
16
Statistics and Data Management, Clovis Oncology, Inc., Boulder, Colorado.
17
Clinical Pharmacology and Nonclinical DMPK, Clovis Oncology, Inc., Boulder, Colorado.
18
Clinical Development, Clovis Oncology, Inc., Boulder, Colorado.
19
Clinical and Preclinical Development, Clovis Oncology, Inc., Boulder, Colorado.
20
Department of Oncology, Sheba Medical Center, Ramat Gan, Israel.

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.

PMID:
28264872
DOI:
10.1158/1078-0432.CCR-16-2796
[Indexed for MEDLINE]
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