Phase I study to assess the safety, Tolerability and pharmacokinetics of AZD4877 in japanese patients with solid tumors

Taito Esaki, Takashi Seto, hiroshi ariyama, Shuji Arita, Chinatsu Fujimoto, Koichiro Tsukasa, Takuro Kometani, Kaname Nosaki, Fumihiko Hirai, Katsuro Yagawa

研究成果: ジャーナルへの寄稿記事

14 引用 (Scopus)

抄録

Introduction. AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods. In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results. Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N=3 in both the 10 and 15mg cohorts, N=6 in both the 20 and 25mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion. AZD4877 up to doses of 25mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

元の言語英語
ページ(範囲)23-31
ページ数9
ジャーナルArchives of Drug Information
4
発行部数2
DOI
出版物ステータス出版済み - 6 1 2011

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Pharmacokinetics
Safety
Neoplasms
Maximum Tolerated Dose
Neutropenia
Terminology
N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide
Febrile Neutropenia
Vital Signs
Leukopenia
Intravenous Infusions
Nausea
Population
Fatigue
Half-Life

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Complementary and alternative medicine

これを引用

Phase I study to assess the safety, Tolerability and pharmacokinetics of AZD4877 in japanese patients with solid tumors. / Esaki, Taito; Seto, Takashi; ariyama, hiroshi; Arita, Shuji; Fujimoto, Chinatsu; Tsukasa, Koichiro; Kometani, Takuro; Nosaki, Kaname; Hirai, Fumihiko; Yagawa, Katsuro.

:: Archives of Drug Information, 巻 4, 番号 2, 01.06.2011, p. 23-31.

研究成果: ジャーナルへの寄稿記事

Esaki, T, Seto, T, ariyama, H, Arita, S, Fujimoto, C, Tsukasa, K, Kometani, T, Nosaki, K, Hirai, F & Yagawa, K 2011, 'Phase I study to assess the safety, Tolerability and pharmacokinetics of AZD4877 in japanese patients with solid tumors', Archives of Drug Information, 巻. 4, 番号 2, pp. 23-31. https://doi.org/10.1111/j.1753-5174.2011.00034.x
Esaki, Taito ; Seto, Takashi ; ariyama, hiroshi ; Arita, Shuji ; Fujimoto, Chinatsu ; Tsukasa, Koichiro ; Kometani, Takuro ; Nosaki, Kaname ; Hirai, Fumihiko ; Yagawa, Katsuro. / Phase I study to assess the safety, Tolerability and pharmacokinetics of AZD4877 in japanese patients with solid tumors. :: Archives of Drug Information. 2011 ; 巻 4, 番号 2. pp. 23-31.
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abstract = "Introduction. AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods. In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results. Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N=3 in both the 10 and 15mg cohorts, N=6 in both the 20 and 25mg cohorts). The most commonly reported AEs were fatigue and nausea (39{\%} of patients each). One patient in each of the 20 and 25mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56{\%}) and leukopenia (44{\%}) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion. AZD4877 up to doses of 25mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.",
author = "Taito Esaki and Takashi Seto and hiroshi ariyama and Shuji Arita and Chinatsu Fujimoto and Koichiro Tsukasa and Takuro Kometani and Kaname Nosaki and Fumihiko Hirai and Katsuro Yagawa",
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T1 - Phase I study to assess the safety, Tolerability and pharmacokinetics of AZD4877 in japanese patients with solid tumors

AU - Esaki, Taito

AU - Seto, Takashi

AU - ariyama, hiroshi

AU - Arita, Shuji

AU - Fujimoto, Chinatsu

AU - Tsukasa, Koichiro

AU - Kometani, Takuro

AU - Nosaki, Kaname

AU - Hirai, Fumihiko

AU - Yagawa, Katsuro

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Introduction. AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods. In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results. Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N=3 in both the 10 and 15mg cohorts, N=6 in both the 20 and 25mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion. AZD4877 up to doses of 25mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

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