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

Kenji Tamura, Jun Hashimoto, Yuko Tanabe, Makoto Kodaira, Kan Yonemori, Takashi Seto, Fumihiko Hirai, Shuji Arita, Gouji Toyokawa, Lan Chen, Hiroshi Yamamoto, Toshio Kawata, Justin Lindemann, Taito Esaki

研究成果: ジャーナルへの寄稿記事

17 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)787-795
ページ数9
ジャーナルCancer chemotherapy and pharmacology
77
発行部数4
DOI
出版物ステータス出版済み - 4 1 2016

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Tumors
Safety
Neoplasms
Pharmacokinetics
Appointments and Schedules
Mutation
4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide
Exanthema
Hyperglycemia
Nausea
Toxicity
Diarrhea

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

これを引用

Tamura, K., Hashimoto, J., Tanabe, Y., Kodaira, M., Yonemori, K., Seto, T., ... Esaki, T. (2016). Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Cancer chemotherapy and pharmacology, 77(4), 787-795. https://doi.org/10.1007/s00280-016-2987-9

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 chemotherapy and pharmacology, 巻 77, 番号 4, 01.04.2016, p. 787-795.

研究成果: ジャーナルへの寄稿記事

Tamura, K, Hashimoto, J, Tanabe, Y, Kodaira, M, Yonemori, K, Seto, T, Hirai, F, Arita, S, Toyokawa, G, Chen, L, Yamamoto, H, Kawata, T, Lindemann, J & Esaki, T 2016, 'Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors', Cancer chemotherapy and pharmacology, 巻. 77, 番号 4, pp. 787-795. https://doi.org/10.1007/s00280-016-2987-9
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. :: Cancer chemotherapy and pharmacology. 2016 ; 巻 77, 番号 4. pp. 787-795.
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abstract = "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.",
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AU - Tamura, Kenji

AU - Hashimoto, Jun

AU - Tanabe, Yuko

AU - Kodaira, Makoto

AU - Yonemori, Kan

AU - Seto, Takashi

AU - Hirai, Fumihiko

AU - Arita, Shuji

AU - Toyokawa, Gouji

AU - Chen, Lan

AU - Yamamoto, Hiroshi

AU - Kawata, Toshio

AU - Lindemann, Justin

AU - Esaki, Taito

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N2 - 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.

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