title: Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
abstract: BACKGROUND
  Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).
  
  
  METHODS
  Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).
  
  
  RESULTS
  Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.
  
  
  CONCLUSIONS
  Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Del Conte
authors.affiliation: 1] Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy [2] Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona Hospital, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Kantonsspital Graubünden, Chur, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: von Moos
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Viganò
authors.affiliation: Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona Hospital, Bellinzona, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Digena
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Locatelli
authors.affiliation: Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona Hospital, Bellinzona, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fasolo
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tessari
authors.affiliation: Kantonsspital Graubünden, Chur, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C468783:H2AX protein, human; D006657:Histones; D010793:Phthalazines; D010879:Piperazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C531550:olaparib