From the protocol abstract.

External beam radiation therapy (EBRT) and concomitant 5-fluorouracil (5FU) chemotharpy (chemoradiation) have been shown to prolong survival in patients with locally-advanced adenocarcinoma of the pancreas. Over the past decade this has been the standard therapy for patients with locally advanced and non-metastatic (or low-volume metastatic) pancreatic cancer. Gemcitabine, a novel nucleoside analogue, was recently introduced and found to both prolong survival duration and increase the percentage of patients who experienced a clinical benefit when compared to 5FU in patients with advanced disease. This finding prompted a Phase I study at MDACC (ID96-080) involving the combination of EBRT and systemic gemcitabine, which served as the foundation for the development of protocol ID98-020 looking at this drug-radiation combination in patients with potentially resectable pancreatic cancer. Improved locaal-regional tumor control in patients with localized pancreatic adenocarcinoma has translated into only a modest improvement in overall survival duration due to liver metastasis being the dominant site of tumor recurrence. The lack of currently available effective systemic therapies for extrapancreatic metastatic disease results in the obvious need to evaluate new agents with unique mechanisms of action. Angiogenesis inhibitors are an attractive class of antineoplastic agents which, theoretically, should be most effective in patients with localized disease or low-volume metastatic disease. Therefore, the intent of this protocol is to combine our most effective local-regional therapy (Gemzar-based chemoradiation) with the anti-angiogenic agent TNP-470 to effect both local disease and the development of systemic (liver) metastasis.

TNP-470 is a synthetic analogue of fumagillin, a natural product secreted by the fungus Aspergillus fumigatus fresenius. Administration of TNP-470 results in a decrease in tumor vascularity, growth of the primary tumor, and the number and size of metastases. TNP-470 has demonstrated anti-tumor activity against several human tumors implanted in nude mice and a recent report from MDACC suggested its efficacy in squamosal carcinoma of the cervix. Therefore, the design of the current study is based upon results of protocol ID96-080 and the finding that improved local-regional therapy must be combined with more effective systemic therapy to improve survival duration. The dose and schedule of administration of TNP-470 is based upon the work of Kudelka and colleagues at this institution.