title: A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
abstract: OBJECTIVE
  To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination.
  
  
  METHODS
  We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m(2) on days 3 and 10, and cisplatin 60 mg/m(2) on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC).
  
  
  RESULTS
  Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤ 2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL-1). No DLTs were seen in six patients at DL-1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration.
  
  
  CONCLUSIONS
  Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Yancey
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.forename: Baskar
authors.initials: B
authors.lastname: Mannargudi
authors.forename: Sukyung
authors.initials: S
authors.lastname: Woo
authors.forename: Shawn
authors.initials: S
authors.lastname: Spencer
authors.forename: William Douglas
authors.initials: WD
authors.lastname: Figg
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; 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; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003841:Deoxycytidine; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C531550:olaparib; D000093542:Gemcitabine