Cargando…

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors

PURPOSE: 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 (ever...

Descripción completa

Detalles Bibliográficos
Autores principales: Tamura, Kenji, Hashimoto, Jun, Tanabe, Yuko, Kodaira, Makoto, Yonemori, Kan, Seto, Takashi, Hirai, Fumihiko, Arita, Shuji, Toyokawa, Gouji, Chen, Lan, Yamamoto, Hiroshi, Kawata, Toshio, Lindemann, Justin, Esaki, Taito
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819940/
https://www.ncbi.nlm.nih.gov/pubmed/26931343
http://dx.doi.org/10.1007/s00280-016-2987-9
_version_ 1782425317447565312
author Tamura, Kenji
Hashimoto, Jun
Tanabe, Yuko
Kodaira, Makoto
Yonemori, Kan
Seto, Takashi
Hirai, Fumihiko
Arita, Shuji
Toyokawa, Gouji
Chen, Lan
Yamamoto, Hiroshi
Kawata, Toshio
Lindemann, Justin
Esaki, Taito
author_facet Tamura, Kenji
Hashimoto, Jun
Tanabe, Yuko
Kodaira, Makoto
Yonemori, Kan
Seto, Takashi
Hirai, Fumihiko
Arita, Shuji
Toyokawa, Gouji
Chen, Lan
Yamamoto, Hiroshi
Kawata, Toshio
Lindemann, Justin
Esaki, Taito
author_sort Tamura, Kenji
collection PubMed
description PURPOSE: 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.
format Online
Article
Text
id pubmed-4819940
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-48199402016-04-11 Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors Tamura, Kenji Hashimoto, Jun Tanabe, Yuko Kodaira, Makoto Yonemori, Kan Seto, Takashi Hirai, Fumihiko Arita, Shuji Toyokawa, Gouji Chen, Lan Yamamoto, Hiroshi Kawata, Toshio Lindemann, Justin Esaki, Taito Cancer Chemother Pharmacol Original Article PURPOSE: 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. Springer Berlin Heidelberg 2016-03-01 2016 /pmc/articles/PMC4819940/ /pubmed/26931343 http://dx.doi.org/10.1007/s00280-016-2987-9 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Tamura, Kenji
Hashimoto, Jun
Tanabe, Yuko
Kodaira, Makoto
Yonemori, Kan
Seto, Takashi
Hirai, Fumihiko
Arita, Shuji
Toyokawa, Gouji
Chen, Lan
Yamamoto, Hiroshi
Kawata, Toshio
Lindemann, Justin
Esaki, Taito
Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title_full Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title_fullStr Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title_full_unstemmed Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title_short Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors
title_sort safety and tolerability of azd5363 in japanese patients with advanced solid tumors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819940/
https://www.ncbi.nlm.nih.gov/pubmed/26931343
http://dx.doi.org/10.1007/s00280-016-2987-9
work_keys_str_mv AT tamurakenji safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT hashimotojun safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT tanabeyuko safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT kodairamakoto safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT yonemorikan safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT setotakashi safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT hiraifumihiko safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT aritashuji safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT toyokawagouji safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT chenlan safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT yamamotohiroshi safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT kawatatoshio safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT lindemannjustin safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors
AT esakitaito safetyandtolerabilityofazd5363injapanesepatientswithadvancedsolidtumors