title: A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187.
abstract: Background Olaparib is an orally available inhibitor of PARP-1. In pre-clinical studies, olaparib was shown to potentiate anti-tumor effects of irinotecan in colon cancer cell lines. This phase I study was conducted to evaluate the safety and tolerability of olaparib in combination with irinotecan. Patients and Methods Patients with advanced colorectal cancer whose disease progressed after at least one systemic therapy regimen were enrolled. Dose escalation and de-escalation were based on toxicity assessment. Pharmacokinetic samples were collected in Cycle 1 for olaparib, irinotecan and SN-38. Results Twenty-five patients were enrolled, 11 patients on a schedule of continuous olaparib and irinotecan every 3 weeks (Part A) and 14 patients on a schedule of intermittent olaparib and irinotecan every 2 weeks (Part B). Continuous olaparib administration was associated with higher than expected toxicities and was not considered to be tolerable. Intermittent olaparib administration was better tolerated, and the recommended phase 2 doses were olaparib 50 mg p.o twice daily days 1-5 and irinotecan 125 mg/m(2) i.v. every 2 weeks. Common toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia and abdominal pain. Nine patients had stable disease as the best response, 2 from Part A (3 and 9 months respectively), and 7 from Part B (median duration: 7.4 months; range: 4 to 13 months). There was no pharmacokinetic interaction between olaparib and irinotecan. Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Ave, Toronto, ON, Canada, M5G 2 M9. eric.chen@uhn.ca.
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.affiliation: Ottawa Health Research Institute, Ottawa, ON, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Ave, Toronto, ON, Canada, M5G 2 M9.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Ave, Toronto, ON, Canada, M5G 2 M9.
authors.forename: Karyn
authors.initials: K
authors.lastname: McKeever
authors.affiliation: Ottawa Health Research Institute, Ottawa, ON, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Keller
authors.affiliation: Ottawa Health Research Institute, Ottawa, ON, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Wells
authors.affiliation: Canadian Cancer Trials Group, Kingston, ON, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Hagerman
authors.affiliation: Canadian Cancer Trials Group, Kingston, ON, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000077146:Irinotecan; C531550:olaparib; D002166:Camptothecin
keywords: Colorectal cancer; Irinotecan; Olaparib; Phase I