Background: c-MET over-expression is associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC)(Kim JH, et al. Oncotarget. 2017;8(42):73098-104). It activates mitogenic signaling, and this may contribute to the limited clinical activity of erlotinib in metastatic PDAC, given the cross talk between EGFR and c-MET(Dulak AM, et al. Oncogene. 2011;30(33):3625-35). Preclinical data suggests that the addition of cabozantinib (a c-MET antagonist) to erlotinib improves anti-tumor activity. The combination in our lab resulted in significant tumor shrinkage, and improvement in survival in a KPC PDAC mouse model compared to treatment with gemcitabine alone. We designed this study to determine the activity of cabozantinib (Cabo) and erlotinib (Eelo) in a population of metastatic PDAC patients whose tumors co-overexpress EGFR and c-MET. Methods: This is an open-label, single arm, Phase II trial of the combination of cabozantinib and erlotinib in metastatic PDAC. Male and female patients > 18years with biopsy proven PDAC and radiologically measurable metastatic disease following progression after first line therapy are eligible. Patients must have tumor tissue available from a surgical resection or archived core biopsy. Only those whose tumors express at least 2+ EGFR and c-MET based on IHC will be allowed on study. ECOG PS2 and above, prior use of Cabo or Erlo, and symptomatic brain metastasis or brain metastasis requiring steroids will exclude patients from this study. Cabo will be administered at 40mg daily dose and Erlo at 100mg daily dose every 28 days without break. The study will be conducted at the Indiana University Simon Cancer Center. The primary objective is to demonstrate at least a 15% radiographic response rate for the combination in the selected population. Secondary objectives include assessment of safety and estimation of PFS, ORR and OS. Based on a Simon two stage design, we will enroll 37 patients in total. If there are no radiologic responses in the 11 patients tested in the first stage, the trial will be closed. The trial opened in November 2017, we have screened 4 patients and enrolled 1. ClinicalTrials.gov Identifier: NCT03213626