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 to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colorectal cancer (mCRC) who progressed or failed prior 5FU, irinotecan, oxaliplatin and/or anti-EGFR therapy received twice daily MEK162 continuously or intermittently in combination with every-2-week FOLFOX without bolus 5-FU. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design. Limited pharmacokinetic (PK) analysis of 5FU and oxaliplatin was performed at the MTD. An additional 6-patient expansion cohort of MEK162, a the defined MTD, was given BID on D1-D5 followed by FOLFOX on Day 6, repeated every 2 weeks. 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. Results: 16 pts were enrolled in the continuous MEK162 arm (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 > 4 m (4-10 m). There were no significant differences in either 5-FU or oxaliplatin PK's with or without MEK162. None of the intermittent MEK162 pts developed a DLT and all 6 progressed at 2 m. Conclusions: The combination of continuous MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated mCRC patients. Clinical trial information: NCT02041481