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, 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
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://ichgcp.net/clinical-trials-registry/NCT02782468.
Keywords: AML; East Asian; MDS; Pevonedistat; Phase 1/1b.
Conflict of interest statement
Hiroshi Handa has received honoraria, consulting fees and grants/funds from Takeda. Yasushi Onishi has received honoraria from Novartis and Pfizer, and grants/funds from Takeda, Novartis, MSD and Janssen. Hiroatsu Iida has received honoraria from Novartis, Janssen, Celgene and Astellas, and grants/funds from Chugai. Yukio Kobayashi has participated on an advisory council/committee for Symbio. Koji Izutsu has received honoraria, consulting fees and grants/funds from Takeda. Xiaofei Zhou is employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda. Helene Faessel is employed by, and owns stocks/shares in, Takeda. Ying Yuan, Farhad Sedarati and Akiko Kimura are employed by Takeda. The other authors declare that they have no competing interests.
© 2022. The Author(s).
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Source: PubMed