Gemcitabine is considered one of the standard drugs for advanced pancreatic cancer and is approved by the FDA to treat it. Cabozantinib is a new drug that has demonstrated effectiveness against pancreatic cancer in laboratory experiments, especially when given with gemcitabine. Initial studies with cabozantinib in pancreatic cancer have shown some activity against the disease. The purpose of this study is to determine the safest and highest dose of cabozantinib that can be given together with standard doses of gemcitabine in patients with pancreatic cancer. This study will determine the safety and tolerability of this two drug combination.

Preclinical work at the University of Michigan has demonstrated that inhibition of c-Met with cabozantinib prevented the development of metastatic disease in an intra-cardiac injection model in NOD/SCID mice. Additionally, the combination of cabozantinib and gemcitabine demonstrated improved tumor control compared to either agent alone in a relevant orthotopic implantation mouse model.

Combining gemcitabine with the c-Met inhibitor cabozantinib in advanced pancreatic cancer is a novel strategy that takes advantage of an established cytotoxic agent with one that targets a pathway known to be important for the growth, dissemination, and resistance of this disease.

Inclusion Criteria:

1. pathologically confirmed pancreatic carcinoma.
2. locally advanced unresectable disease, metastatic disease, or recurrent disease following surgical therapy.
3. ≥ 18 years old.
4. Life expectancy of greater than 12 weeks.
5. ECOG performance status ≤1 (Karnofsky ≥70%) (See Appendix A).
6. adequate organ and marrow function as follows:
7. capable of understanding and complying with the protocol requirements and has signed the informed consent document.
8. use medically accepted barrier methods of contraception
9. women of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

1. neuroendocrine tumors of the pancreas.
2. more than 1 prior systemic treatment regimen for pancreatic cancer. may have received prior neoadjuvant or adjuvant therapy, including gemcitabine, provided 6 months have elapsed from completion of that treatment and the start of study therapy.
3. Previous gemcitabine therapy for advanced pancreatic cancer. Patients who have had chemotherapy within 4 weeks, nitrosoureas/mitomycin C within 6 weeks, or monoclonal antibody within 6 weeks prior to planned initiation of study treatment.
4. prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.
5. have received an investigational agent within 28 days of the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is longer.
6. have received radiation therapy within 14 days of study treatment.
7. have not recovered from toxicity due to all prior therapies (i.e., return to pretherapy baseline or to CTCAE Grade 0 or 1) except alopecia and non-clinically significant AEs.
8. known brain metastases.

The MTD could not be determined as too many patients experienced toxicity.