Background: 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. Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. A similar TKI, regorafenib, has recently demonstrated efficacy as monotherapy in advanced mCRC. Demonstrating activity of this class of compounds with standard cytotoxic therapy represents a clinical unmet need for patients (pts) with mCRC. 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/m²PO 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: 24 of 43 planned pts have received therapy. 19 were white and 17 male. Median age 61y (37-79). 14 (58%) were KRAS-mut. Median prior lines of therapy for mCRC was 3 (1-5). All but one had liver and/or lung metastases. Most frequently observed adverse events (AEs) included fatigue (29%), HTN (38%), and HFS (91%). 18 pts (75%) had a grade 3 AE (11/18 were HFS). There were no grade 4 or 5 toxicities. Preliminary PFS is 4.1m. 5/16 (31%) evaluable pts have radiographic stable disease. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Preliminary PFS data appears promising in this refractory mCRC population. Clinical trial information: NCT01471353.