Background: Based on available data, a reasonable upfront treatment for elderly mCRC pts is a fluoropyrimidine-based monotherapy plus bevacizumab, irrespectively of RAS status. Up today, data about the treatment of elderly mCRC pts with chemotherapy plus anti-EGFRs are scarce. FOLFOX plus pan is a standard first-line option for RAS wt mCRC. Adjustments of chemo-dosage are commonly applied in routinary practice to elderly pts, while evidences about the combination of an anti-EGFR with a fluoropyrimidine-based monotherapy are lacking. On the basis of these considerations, we designed the present randomized phase II trial of upfront pan in combination with FOLFOX or 5FU (both at adjusted dosage) in elderly RAS and BRAFwt unresectable mCRC pts. Methods: This is a prospective, open-label, multicenter phase II trial in which initially unresectable and previously untreated elderly (≥ 70 years) RAS and BRAF wt mCRC pts are randomized to pan (6 mg/kg) plus simplified FOLFOX (oxaliplatin 85 mg/sqm, L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion) or 5FU (L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion) every 14 days up to 12 cycles, followed by pan alone until disease progression. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 screening tool and CRASH score is scheduled at baseline. Primary endpoint is progression-free survival (PFS). Secondary endpoints are response rate, overall survival, safety profile, early response, association of G8 score with clinical outcome and treatment-related toxicity, association of CRASH score risk categories with treatment-related toxicity. Assuming an expected median PFS time ≥ 9.65 months with one or both experimental regimens, a sample size of 90 patients in each arm will guarantee a power of 90% for a one-sided Brookmeyer-Crowley test, with a type I error rate of 5%, against the null hypothesis of a median PFS time ≤ 6 months. A pick-the-winner strategy will drive further experimental developments for one or both the two combinations. The study is sponsored by GONO Cooperative Group. EUDRACT 2015-003888-10. Clinical trial information: 2015-003888-10.