title: Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies.
  
  
  METHODS
  AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients.
  
  
  RESULTS
  Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years.
  
  
  CONCLUSIONS
  Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. ketamura@ncc.go.jp.
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: Jun
authors.initials: J
authors.lastname: Hashimoto
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
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 Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
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: Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Arita
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.affiliation: Research and Development, AstraZeneca KK, Osaka, Japan.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Research and Development, AstraZeneca KK, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Research and Development, AstraZeneca KK, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kawata
authors.affiliation: AstraZeneca Innovative Medicines Unit, Cambridge, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Lindemann
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
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib
keywords: AZD5363; Akt inhibitor; Akt1 (E17K) mutation; Safety; Solid tumor