title: An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib.
abstract: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation.
  
  
  
  Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers.
  
  
  
  Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts.
  
  
  
  The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day.
  
  
  
  NCT00777582 (ClinicalTrials.gov).
authors.affiliation: Drug Development Unit, The Royal Marsden/The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mateo
authors.affiliation: Drug Development Unit, The Royal Marsden/The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK.
authors.forename: V
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Drug Development Unit, The Royal Marsden/The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Clinical Trials Unit, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Dean
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Prince of Wales Hospital, Randwick, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, UK.
authors.forename: C
authors.initials: C
authors.lastname: Gourley
authors.affiliation: Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Mount Vernon Hospital, Northwood, UK.
authors.forename: G
authors.initials: G
authors.lastname: Rustin
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Leunen
authors.affiliation: UCL Hospitals and UCL Cancer Institute, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ledermann
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: H
authors.initials: H
authors.lastname: Swaisland
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fielding
authors.affiliation: PHASTAR, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: Bannister
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Nicum
authors.affiliation: Drug Development Unit, The Royal Marsden/The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK. maria.bynoe@icr.ac.uk.
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
mesh_terms: D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib