Purpose: Multi-tyrosine kinase inhibitors have shown clinical activity in metastatic colorectal cancer patients. Cabozantinib, a multi-tyrosine kinase inhibitor, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This Phase II study aimed to investigate cabozantinib, a multityrosine kinase inhibitor, in refractory, metastatic colorectal cancer patients. Patients and Methods: A non-randomized, two-stage, phase 2 clinical trial evaluating 12 week PFS was conducted in 8 cancer centers across the United States between May 2018 and July 2020. Results: A total of 44 patients were enrolled between May 2018-May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five Grade 5 AEs were reported of which 4 were unrelated to study drug and 1 was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (CI 0.29-0.62; p<0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median OS was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type,11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild type tumors compared to RAS mutant tumors (0.61 vs 0.32, p=0.11). Conclusions: This phase 2 study demonstrated clinical activity of cabozantinib in heavily pretreated, refractory mCRC patients, and supports further investigation.