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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 [ 14 C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [ 14 C]-pevonedistat 25 mg/m 2 . In part B (n = 7), patients received pevonedistat 25 or 20 mg/m 2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m 2 or carboplatin AUC5 plus paclitaxel 175 mg/m 2 on day 1 every 3 weeks. Following the single dose of [ 14 C]-pevonedistat 25 mg/m 2 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 .

investigational new drugs

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