title: A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with GermlineBRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors.
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 germlineBRCA1/2mutation 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 germlineBRCA1/2-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 germlineBRCA1/2-mutated HGOC.Clin Cancer Res; 23(15); 4095-106. ©2017 AACR.
authors.affiliation: Research Department of Oncology, UCL Cancer Institute, London, United Kingdom. r.kristeleit@ucl.ac.uk.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Department of Medical Oncology, Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, Tennessee.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Department of Obstetrics and Gynecology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Department of Medical Oncology, Yale University, New Haven, Connecticut.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Department of Medical Oncology, Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, Florida.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Department of Medical Oncology, Basser Center for BRCA, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.affiliation: Department of Medical Oncology, Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drew
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: Lee-May
authors.initials: LM
authors.lastname: Chen
authors.affiliation: Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Safra
authors.affiliation: Department of Medical Oncology, Guy's Hospital, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Montes
authors.affiliation: Clinical Science, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Heidi
authors.initials: H
authors.lastname: Giordano
authors.affiliation: Clinical Science, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Lara
authors.initials: L
authors.lastname: Maloney
authors.affiliation: Biostatistics, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Sandra
authors.initials: S
authors.lastname: Goble
authors.affiliation: Statistics and Data Management, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Jeff
authors.initials: J
authors.lastname: Isaacson
authors.affiliation: Clinical Pharmacology and Nonclinical DMPK, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Clinical Development, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Jen
authors.initials: J
authors.lastname: Borrow
authors.affiliation: Clinical and Preclinical Development, Clovis Oncology, Inc., Boulder, Colorado.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Rolfe
authors.affiliation: Department of Oncology, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Shapira-Frommer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib