Phase I study assessing the mass balance, pharmacokinetics, and excretion of [ 14 C]-pevonedistat, a NEDD8-activating en
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PHASE I STUDIES
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 1 & Farhad Sedarati 1 & Douglas V. Faller 1 & Dan Zhao 1 & Hélène M. Faessel 1 & Swapan Chowdhury 1 & Jayaprakasam Bolleddula 1 & Yuexian Li 1 & Karthik Venkatakrishnan 1 & Zsuzsanna Papai 2 Received: 20 July 2020 / Accepted: 6 October 2020 # The Author(s) 2020
Summary 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 pevonedistat . advanced solid tumors . phase I . mass balance . pharmacokinetics . elimination
Introduction Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the neural precursor cellexpressed, developmentally down-regulated 8 (NEDD8)-
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-01017-x) contains supplementary material, which is available to authorized users. * Xiaofei Zhou [email protected] 1
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139, USA
2
Medical Center Hungarian Defense Forces, Budapest, Hungary
activating enzyme (NAE) [1, 2]. NAE conjugates NEDD8 to cullin-RING ligases (CRLs), which control ubiquitination and proteasomal degradation of substrates involved in cell cycle progression (p21,
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