Phase I Study of the Investigational NEDD8-activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
Mené sur 48 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale du pévonédistat, un inhibiteur de l'enzyme activatrice de NEDD8
Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced non-hematological malignancies Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on Days 1-5 (schedule A, n=12), or Days 1, 3, and 5 (schedules B, n=17, and C, n=19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg prior to each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0 Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via immunohistochemical detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a Day 1, 3, 5 schedule every 3 weeks with an MTD between 50 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated pevonedistat tumor NAE inhibition. Clinical trials are ongoing.