Background: MEK inhibition is of interest in cancer drug development. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We conducted an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628/NCT02188264) of selumetinib and CsA combination. Biomarkers of response are being co-developed. Methods: Patients with advanced solid tumors were treated with the combination of selumetinib and CsA in dose escalation followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilized a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: As of January 2017, 18 patients were enrolled in the dose escalation phase and 20 patients were enrolled in the dose expansion phase. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three DLTs - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was identified as selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. The selumetinib “run-in” did not favor a specific RAS type. Two partial responses were noted. Sixteen patients had stable disease, and 6 patients had progression of disease as their best response to therapy. Conclusions: Selumetinib in combination with cyclosporin A appears to be well tolerated with evidence of activity in mCRC. Tumor response data are currently being updated. FZD will be evaluated as a potential biomarker of response. Clinical trial information: NCT02188264