title: Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours.
abstract: OBJECTIVE
  This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed.
  
  
  METHODS
  In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation.
  
  
  RESULTS
  Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response.
  
  
  CONCLUSIONS
  Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies.
  
  
  BACKGROUND
  NCT01813474.
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kyonemor@ncc.go.jp.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodaira
authors.affiliation: Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Fujikawa
authors.affiliation: Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sagawa
authors.affiliation: Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Taito
authors.initials: T
authors.lastname: Esaki
authors.affiliation: Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shirakawa
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hirai
authors.affiliation: AstraZeneca R and D, Osaka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yokoi
authors.affiliation: AstraZeneca R and D, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kawata
authors.affiliation: AstraZeneca R and D, Osaka, Japan.
authors.forename: Ben
authors.initials: B
authors.lastname: Hatano
authors.affiliation: Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013607:Tablets
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013607:Tablets; C531550:olaparib
keywords: Clinical trial, Phase I; Olaparib; Poly(ADP-ribose) polymerase inhibitors; Safety; Solid tumours