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
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, condu...
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-022-01264-w |
| _version_ | 1818210314126098432 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hiroshi Handa |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-12T05:14:38Z |
| format | Article |
| id | doaj.art-16e57d9cb04a4e2ea784bdfdd8aa57cf |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-12T05:14:38Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-16e57d9cb04a4e2ea784bdfdd8aa57cf2022-12-22T00:36:48ZengBMCJournal of Hematology & Oncology1756-87222022-05-011511510.1186/s13045-022-01264-wPevonedistat 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 azacitidineHiroshi Handa0June-Won Cheong1Yasushi Onishi2Hiroatsu Iida3Yukio Kobayashi4Hyeoung-Joon Kim5Tzeon-Jye Chiou6Koji Izutsu7Olga Tsukurov8Xiaofei Zhou9Helene Faessel10Ying Yuan11Farhad Sedarati12Douglas V. Faller13Akiko Kimura14Shang-Ju Wu15National University Corporation, Gunma UniversitySeverence Hospital, Yonsei University Health SystemNational University, Corporation Tohoku UniversityNational Hospital Organization Nagoya Medical CenterInternational University of Health and Welfare, Mita HospitalChonnam National University, Hwasun HospitalTaipei Municipal Wanfang Hospital, Taipei Medical University, Taipei Veterans General HospitalNational Cancer Center HospitalTakeda Development Center Americas, Inc. (TDCA)Takeda Development Center Americas, Inc. (TDCA)Takeda Development Center Americas, Inc. (TDCA)Takeda Development Center Americas, Inc. (TDCA)Takeda Development Center Americas, Inc. (TDCA)Takeda Development Center Americas, Inc. (TDCA)Takeda Pharmaceutical Company LimitedDivision of Hematology, Department of Internal Medicine, Zhongzheng Dist, National Taiwan University HospitalAbstract 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/NCT02782468https://doi.org/10.1186/s13045-022-01264-wAMLMDSPevonedistatPhase 1/1bEast Asian |
| spellingShingle | 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 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 & Oncology AML MDS Pevonedistat Phase 1/1b East Asian |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | AML MDS Pevonedistat Phase 1/1b East Asian |
| url | https://doi.org/10.1186/s13045-022-01264-w |
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