Phase I study of pevonedistat combined with capecitabine and oxaliplatin in patients with platinum-refractory advanced gastric cancer.

Pevonedistat, a potent NEDD8-activating enzyme inhibitor, has shown preclinical promise in overcoming platinum resistance and enhancing antitumor activity. This phase I study investigated the recommended dose (RD) and tolerability of pevonedistat in combination with capecitabine plus oxaliplatin (CapeOX) as third-line or later treatment in patients with unresectable advanced or recurrent gastric cancer (AGC). The study included a dose-finding cohort for determining the RD and an expansion cohort for assessing the efficacy and safety at the RD. Twelve patients were enrolled between April 2019 and September 2021. Dose-limiting toxicities (DLTs), including grade 2/3 aspartate transaminase/alanine transaminase (AST/ALT) elevation and treatment delays, occurred in the initial 2 patients at level 1 (20 mg/m). After protocol amendment, no DLTs were observed at level 0 (15 mg/m), which was determined as the RD. Common adverse events were decreased platelet count (67%), nausea (58%), and AST/ALT elevation (58%). A partial response was achieved in 2 patients (17%) and disease control was achieved in 8 (67%). Median overall survival was 9.3 months and progression-free survival was 4.4 months. Pevonedistat plus CapeOX was well tolerated and showed promising efficacy as salvage-line chemotherapy for AGC.