Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo 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 factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The 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 in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773.