A phase I study of the MEK inhibitor trametinib combined with the MDM2 inhibitor HDM201 in RAS/RAF mutant advanced colorectal cancer

RAS/RAF mutant advanced colorectal cancer (CRC) is associated with poor outcomes and limited therapeutic options. Preclinical studies suggest that combining MEK and MDM2 inhibition may yield synergistic effects. This dose-escalation, phase I study evaluated the safety of escalating doses of the MDM2 inhibitor HDM201 combined with the MEK inhibitor trametinib at a fixed dose. KRAS or BRAF mutant/ TP53 wild-type advanced CRC patients received oral trametinib once daily and oral HDM201 on days 1 and 8 of a 28-day cycle. The primary endpoint was the maximum tolerated dose (MTD), estimated using the time-to-event Continual Reassessment Method (TITE-CRM). From December 2018 to February 2023, 11 patients received the experimental treatment. The study was prematurely discontinued in July 2023 due to slow accrual. Five (45%) patients experienced grade 3 treatment-related AEs (TRAE). Most common TRAEs were dermatitis acneiform ( n = 9, 82%), diarrhea ( n = 8, 73%), and fatigue ( n = 7, 64%). No objective responses were reported. The safety profile of the combination was consistent with the known safety profile of each drug. The small sample size and early study discontinuation prevent any definitive conclusions. NCT03714958.