Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

Xiaofei Zhou, Farhad Sedarati, Douglas V Faller, Dan Zhao, Hélène M Faessel, Swapan Chowdhury, Jayaprakasam Bolleddula, Yuexian Li, Karthik Venkatakrishnan, Zsuzsanna Papai, Xiaofei Zhou, Farhad Sedarati, Douglas V Faller, Dan Zhao, Hélène M Faessel, Swapan Chowdhury, Jayaprakasam Bolleddula, Yuexian Li, Karthik Venkatakrishnan, Zsuzsanna Papai

Abstract

Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366 .

Keywords: advanced solid tumors; elimination; mass balance; pevonedistat; pharmacokinetics; phase I.

Conflict of interest statement

Xiaofei Zhou declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Farhad Sedarati declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Douglas V. Faller declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Swapan Chowdhury declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Yuexian Li declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Hélène M. Faessel declares employment with, and ownership of stocks/shares in Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Jayaprakasam Bolleddula declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited at the time of the study. Karthik Venkatakrishnan declares employment with Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited at the time of the study. Zsuzsanna Papai declares no conflict of interest.

Figures

Fig. 1
Fig. 1
Mean concentration–time profiles of pevonedistat and total radioactivity (drug-related material) in plasma following a single infusion of [14C]-pevonedistat 25 mg/m2
Fig. 2
Fig. 2
Mean concentration–time profiles of pevonedistat in plasma and whole blood following a single infusion of [14C]-pevonedistat 25 mg/m2
Fig. 3
Fig. 3
Mean time course of cumulative excretion of total radioactivity (drug-related material) in urine and feces following a single infusion of [14C]-pevonedistat 25 mg/m2

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