A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil in Metastatic Colorectal Adenocarcinoma

The purpose of this phase I trial was to determine the recommended phase II dose for the combination of cabozantinib and trifluridine/tipiracil in 15 patients with colorectal cancer. The results demonstrate that the combination of both drugs is tolerable with the use of prophylactic growth factors. The observed preliminary efficacy warrants further evaluation. Introduction: This study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with tr iflur idine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC). Patients and Methods: Single institution investigator-initiated phase 1 study using 3 + 3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed. Results: Fifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%. Conclusion: The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC. ClinicalTrials.Gov: NCT04868773.