Background: Both panitumumab (Pmab), the anti-EGFR antibody and TAS-102, the combination drug of trifluridine and tipiracil are approved agents for the treatment of metastatic colorectal cancer (mCRC). In preclinical models, the combination of Pmab with TAS-102 demonstrated enhanced activities compared with either drug alone. This phase I/II study is designed to investigate the safety and efficacy of Pmab combined with TAS-102 in patients (pts) with RAS (KRAS/NRAS) wild-type mCRC refractory to standard chemotherapies. Here we reported the results of phase I part. Methods: Eligible pts are aged 20-74 y, ECOG performance status (PS) 0-1 with confirmed RAS wild-type mCRC, and refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin and anti-angiogenesis therapy, and had no prior treatment with anti-EGFR antibody, TAS-102 or regorafenib. Phase I part is designed to evaluate the incidence of dose limiting toxicities (DLTs) during the first course and to determine recommended phase II dose (RP2D) in the dose de-escalation design (3 + 3 manner) of Pmab (6 mg/kg on days 1 and 15, every 4 weeks per course) combined with TAS-102 (35 mg/m² BID on days 1-5 and 8-12, every 4 weeks). DLTs were defined as drug-related adverse events (AEs) as follows; febrile neutropenia, G4 neutropenia > 7days, G4 thrombocytopenia, inability to start the 2nd course more than 14 days delay, and G3/4 non-hematological toxicities. Results: Seven pts (3 male, 4 female) with a median age of 68 (range 57-71) were enrolled. Pts were ECOG PS 0 (3/7) or 1 (4/7) with primary tumor located in the colon (3/7) or rectum (4/7). One pt was excluded for the DLT evaluation due to protocol deviation. No DLT was observed in the 6 DLT-evaluable pts. Most frequent drug-related AEs during the DLT evaluation period were G2/3 neutropenia, G1/2 stomatitis, G1 nausea, G1 anorexia and G1/2 rash. Three pts achieved a partial response, and 3 pts had a stable disease. Conclusions: The RP2D for Pmab combined with TAS-102 was determined as the standard dose of Pmab and TAS-102. The enrollment of phase II part is ongoing to evaluate the PFS rate at 6 months by investigator assessment as a primary endpoint with the target number of 46 pts. Clinical trial information: 02613221.