A Trial of Cabozantinib (XL184) and Gemcitabine in Advanced Pancreatic Cancer

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

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

Exclusion criteria

• neuroendocrine tumors of the pancreas.
• 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.
• 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.
• 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.
• 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.
• have received radiation therapy within 14 days of study treatment.
• 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.
• known brain metastases.