Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine

Hiroshi Handa; June Won Cheong; Yasushi Onishi; Hiroatsu Iida; Yukio Kobayashi; Hyeoung Joon Kim; Tzeon Jye Chiou; Koji Izutsu; Olga Tsukurov; Xiaofei Zhou; Helene Faessel; Ying Yuan; Farhad Sedarati; Douglas V. Faller; Akiko Kimura; Shang Ju Wu

doi:10.1186/s13045-022-01264-w

Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine

Hiroshi Handa, June Won Cheong, Yasushi Onishi, Hiroatsu Iida, Yukio Kobayashi, Hyeoung Joon Kim, Tzeon Jye Chiou, Koji Izutsu, Olga Tsukurov, Xiaofei Zhou, Helene Faessel, Ying Yuan, Farhad Sedarati, Douglas V. Faller, Akiko Kimura, Shang Ju Wu

臺北市立萬芳醫院

研究成果: 雜誌貢獻 › 快報 › 同行評審

1 引文斯高帕斯（Scopus）

摘要

Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468

原文	英語
文章編號	56
期刊	Journal of Hematology and Oncology
卷	15
發行號	1
DOIs	https://doi.org/10.1186/s13045-022-01264-w
出版狀態	已發佈 - 12月 2022

ASJC Scopus subject areas

分子生物學
血液學
腫瘤科
癌症研究

UN SDG

此研究成果有助於以下永續發展目標

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10.1186/s13045-022-01264-w

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引用此

Handa, H., Cheong, J. W., Onishi, Y., Iida, H., Kobayashi, Y., Kim, H. J., Chiou, T. J., Izutsu, K., Tsukurov, O., Zhou, X., Faessel, H., Yuan, Y., Sedarati, F., Faller, D. V., Kimura, A., & Wu, S. J. (2022). Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine. Journal of Hematology and Oncology, 15(1), [56]. https://doi.org/10.1186/s13045-022-01264-w

Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine. / Handa, Hiroshi; Cheong, June Won; Onishi, Yasushi 等.
於: Journal of Hematology and Oncology, 卷 15, 編號 1, 56, 12.2022.

研究成果: 雜誌貢獻 › 快報 › 同行評審

Handa, H, Cheong, JW, Onishi, Y, Iida, H, Kobayashi, Y, Kim, HJ, Chiou, TJ, Izutsu, K, Tsukurov, O, Zhou, X, Faessel, H, Yuan, Y, Sedarati, F, Faller, DV, Kimura, A & Wu, SJ 2022, 'Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine', Journal of Hematology and Oncology, 卷 15, 編號 1, 56. https://doi.org/10.1186/s13045-022-01264-w

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abstract = "Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468",

keywords = "AML, East Asian, MDS, Pevonedistat, Phase 1/1b",

author = "Hiroshi Handa and Cheong, {June Won} and Yasushi Onishi and Hiroatsu Iida and Yukio Kobayashi and Kim, {Hyeoung Joon} and Chiou, {Tzeon Jye} and Koji Izutsu and Olga Tsukurov and Xiaofei Zhou and Helene Faessel and Ying Yuan and Farhad Sedarati and Faller, {Douglas V.} and Akiko Kimura and Wu, {Shang Ju}",

note = "Funding Information: The authors would like to acknowledge all patients who participated in this study and their families, as well as all the investigators and site staff who made the study possible. We thank Qiang Wang from PPD, who served as the medical monitor for this study. The authors acknowledge Helen Kitchen, PhD, and Helen Wilkinson, PhD, of Ashfield MedComms, an Ashfield Health company, for medical writing support for the development of this manuscript under the direction of the authors, which was funded by Takeda Pharmaceuticals, U.S.A., Inc., and complied with the Good Publication Practice 3 ethical guidelines (Battisti WP, et al. Ann Intern Med 2015;163:461–4), and editorial support from Marcel Kuttab, PharmD (Takeda Pharmaceuticals U.S.A., Inc.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13045-022-01264-w",

language = "English",

volume = "15",

journal = "Journal of Hematology and Oncology",

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T1 - Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes

T2 - a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine

AU - Handa, Hiroshi

AU - Cheong, June Won

AU - Onishi, Yasushi

AU - Iida, Hiroatsu

AU - Kobayashi, Yukio

AU - Kim, Hyeoung Joon

AU - Chiou, Tzeon Jye

AU - Izutsu, Koji

AU - Tsukurov, Olga

AU - Zhou, Xiaofei

AU - Faessel, Helene

AU - Yuan, Ying

AU - Sedarati, Farhad

AU - Faller, Douglas V.

AU - Kimura, Akiko

AU - Wu, Shang Ju

N1 - Funding Information: The authors would like to acknowledge all patients who participated in this study and their families, as well as all the investigators and site staff who made the study possible. We thank Qiang Wang from PPD, who served as the medical monitor for this study. The authors acknowledge Helen Kitchen, PhD, and Helen Wilkinson, PhD, of Ashfield MedComms, an Ashfield Health company, for medical writing support for the development of this manuscript under the direction of the authors, which was funded by Takeda Pharmaceuticals, U.S.A., Inc., and complied with the Good Publication Practice 3 ethical guidelines (Battisti WP, et al. Ann Intern Med 2015;163:461–4), and editorial support from Marcel Kuttab, PharmD (Takeda Pharmaceuticals U.S.A., Inc.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468

AB - Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468

KW - AML

KW - East Asian

KW - MDS

KW - Pevonedistat

KW - Phase 1/1b

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AN - SCOPUS:85129992525

SN - 1756-8722

VL - 15

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

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Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine

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ASJC Scopus subject areas

UN SDG

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