A phase IB study of the combination of selumetinib (AZD6244, ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).

2587Background: 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 co...