Background: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting < 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n = 1), CPK elevation (n = 2), neutropenia (n = 1), peripheral neuropathy (n = 3), thrombocytopenia (n = 1), retinal vascular disorder (n = 1), and acneiform rash (n = 1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of > 5 months (5-10 months). There were no significant differences in the PKs of 5FU or oxaliplatin when administered with or without MEK162. Conclusions: The combination of MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. Clinical trial information: NCT02041481