title: Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.
abstract: BACKGROUND
  Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects.
  
  
  METHODS
  In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)).
  
  
  RESULTS
  Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase.
  
  
  CONCLUSIONS
  Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study.
  
  
  BACKGROUND
  NCT00515866.
authors.affiliation: Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville. Electronic address: jbendell@tnonc.com.
authors.forename: J
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: O'Reilly
authors.affiliation: Department of Oncology, University of Oxford, Oxford.
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Department of Medicine, Royal Marsden Hospital, Sutton, UK.
authors.forename: I
authors.initials: I
authors.lastname: Chau
authors.affiliation: Yale Cancer Center, Yale School of Medicine, New Haven, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hochster
authors.affiliation: Global Medicines Development, AstraZeneca.
authors.forename: A
authors.initials: A
authors.lastname: Fielding
authors.affiliation: Clinical Pharmacology, AstraZeneca, Macclesfield, UK.
authors.forename: W
authors.initials: W
authors.lastname: Burke
authors.affiliation: Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.
authors.forename: H
authors.initials: H
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011379:Prognosis; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D010793:Phthalazines; D010879:Piperazines; D003841:Deoxycytidine; C531550:olaparib; D000093542:Gemcitabine
keywords: gemcitabine; olaparib; pancreatic cancer