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, 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).

Figures

Fig. 1

Treatment responses in the response-evaluable populationa (N = 19): a Swimmer plot showing responses and duration of treatmentb; Best percentage change from baseline in myeloblast count in b patients with AMLc and c patients with MDSd. AE, adverse event; AML, acute myeloid leukemia; CB, clinical benefit; CR, complete remission; CRi, complete remission with incomplete blood count recovery; HSCT, hematopoietic stem cell transplant; mCR, marrow complete remission; MDS, myelodysplastic syndromes; PD, progressive disease; PR, partial remission; SD, stable disease. aAll patients who received at least one dose of study drug, had a baseline disease assessment, and had at least one post-baseline disease assessment. bFor patients who were ongoing treatment at data cut-off and who therefore did not have a date of last visit, their date of last assessment was used to determine bar length. TP53 mutation status is indicated for the 4 patients with available data. Mutation status was unknown in the remaining patients. cTwo patients with AML in the single-agent pevonedistat 44 mg/m2 dose cohort and one patient with AML in the pevonedistat 10 mg/m2 combination arm dose cohort were excluded due to insufficient bone marrow aspirate blast data. The patient with AML with a decrease in blast count and stable disease had an abnormal cytogenetic finding at screening; stable disease was recorded on cycle 1 day 15 on November 27, 2017, and lasted to the end of study on December 7, 2017. The patient discontinued the study to initiate a hematopoietic stem cell transplant. dOne patient with MDS in the pevonedistat 20 mg/m2 combination arm dose cohort was excluded due to insufficient bone marrow aspirate blast data