Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. A similar TKI, regorafenib, has efficacy as monotherapy in advanced mCRC. Demonstrating activity of this compound class with standard cytotoxic therapy represents a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m² PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 29 of 43 planned pts have received therapy and the first 26 are included in this planned interim analysis. Baseline pt demographics are in the Table. Most frequently observed adverse events (any AE) included HTN (15%), diarrhea (35%), fatigue (65%) and HFS (91%). 19 pts (73%) had a grade 3 AE (12/19 were HFS). There were no grade 4 or 5 toxicities. 11/25 (44%) evaluable pts have radiographic stable disease. With a median f/u of 6.2 mo, interim PFS is 4.4m. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Planned interim PFS data appears promising in this refractory mCRC population. Molecular correlatives for predictors of response are being analyzed. Clinical trial information: NCT01471353.