Background: FTD/TPI is an oral antineoplastic agent that was developed to overcome resistance to fluoropyrimidines. FTD/TPI is approved for use in previously treated patients with mCRC. This Phase I expansion study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of FTD/TPI and IRI with BEV. The dose-escalation phase determined the maximum tolerated dose of FTD/TPI and IRI to be FTD/TPI 25 mg/m² and IRI 180 mg/m². Methods: Patients aged ≥18 years with mCRC with disease progression following ≥1 line of chemotherapy were included. Patients who had required any prior IRI dose reductions, dose delay, or growth factor support in the first 8 weeks of treatment with IRI were excluded. FTD/TPI was administered at 25 mg/m² twice daily on days 1-5 of 14-day cycles with IRI 180 mg/m² preceded by BEV 5 mg/kg on day 1 of each 14-day cycle. PK samples were collected on days 1-3 of cycle 1. Results: Twenty-four patients with mCRC were enrolled; 67% were female and the median age was 55.5 years (range 19-73). The median number of prior regimens was 4; all patients had received prior fluoropyrimidine and oxaliplatin treatment, 3 patients were IRI-naïve, and 5 patients were BEV-naïve. Grade ≥3 adverse events were reported in 20 patients (83%); the most common were neutropenia (33%), leukopenia (25%), diarrhea (13%), and hypertension (13%). Based on RECIST v1.1 of the 24 evaluable patients, 3 had a partial response and 17 experienced stable disease. Median progression-free survival was 7.9 months (95% CI 5.1, 13.4). PK analysis did not show any significant correlation between the plasma concentrations of FTD/TPI and IRI or their metabolites. Conclusions: No new safety findings or cumulative adverse events were reported with the addition of BEV to FTD/TPI and IRI. Preliminary efficacy results indicate promising anti-tumor activity using FTD/TPI and IRI with BEV for patients who had failed a median of 4 prior regimens with most having had prior IRI. This triple chemotherapy combination warrants further evaluation in patients with mCRC. Clinical trial information: NCT01916447