title: A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.
abstract: BACKGROUND
  Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment.
  
  
  METHODS
  Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells.
  
  
  RESULTS
  The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma.
  
  
  CONCLUSIONS
  This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.
authors.affiliation: University of Oxford Department of Oncology, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK.
authors.forename: O A
authors.initials: OA
authors.lastname: Khan
authors.forename: M
authors.initials: M
authors.lastname: Gore
authors.forename: P
authors.initials: P
authors.lastname: Lorigan
authors.forename: J
authors.initials: J
authors.lastname: Stone
authors.forename: A
authors.initials: A
authors.lastname: Greystoke
authors.forename: W
authors.initials: W
authors.lastname: Burke
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: A J
authors.initials: AJ
authors.lastname: Watson
authors.forename: G
authors.initials: G
authors.lastname: McGown
authors.forename: M
authors.initials: M
authors.lastname: Thorncroft
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
authors.forename: R
authors.initials: R
authors.lastname: Califano
authors.forename: J
authors.initials: J
authors.lastname: Larkin
authors.forename: S
authors.initials: S
authors.lastname: Wellman
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C531550:olaparib