title: A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours.
abstract: BACKGROUND
  This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.
  
  
  METHODS
  Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.
  
  
  RESULTS
  Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml-1min-1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.
  
  
  CONCLUSIONS
  Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.|Northern Ireland Cancer Center, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, UK.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
authors.affiliation: Beatson West of Scotland Cancer Centre, and Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Tr Jeffry
authors.initials: TJ
authors.lastname: Evans
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Churchill Hospital, and Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Drug Development Unit, Royal Marsden Hospital/Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Division of Cancer Studies, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: James
authors.initials: J
authors.lastname: Spicer
authors.affiliation: Department of Medical Oncology, Institut Curie, 26, rue d'Ulm, Paris 75005 France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dieras
authors.affiliation: Beatson West of Scotland Cancer Centre, and Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Roxburgh
authors.affiliation: Clovis Oncology, Inc., Boulder, 5500 Flatiron Parkway, Boulder, CO 80301, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Giordano
authors.affiliation: Clovis Oncology, Inc., Boulder, 5500 Flatiron Parkway, Boulder, CO 80301, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jaw-Tsai
authors.affiliation: Clovis Oncology, Inc., Boulder, 5500 Flatiron Parkway, Boulder, CO 80301, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Goble
authors.affiliation: Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, High Heaton, Newcastle Upon Tyne NE7 7DN, UK.|Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D007211:Indoles; D015251:Epirubicin; C531549:rucaparib; D003520:Cyclophosphamide; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin