Tolfenamic Acid, Gemcitabine and Radiation for Locally Advanced or Metastatic Pancreatic Cancer Requiring Radiation

The purposes of this study are to:

* Evaluate the safety and toxicity of tolfenamic acid when used with gemcitabine and radiation therapy in patients with locally advanced or metastatic pancreatic cancer.
* Determine the maximum-tolerated dose (MTD) of tolfenamic acid when used with gemcitabine and radiation in pancreatic cancer.
* Characterize the pharmacokinetic profile of tolfenamic acid when used with gemcitabine and radiation.
* Assess the anti-tumor response to tolfenamic acid when used with gemcitabine and radiation in patients with advanced pancreatic malignancies.

This is a phase I, open-label, non-randomized, single-center, dose-escalation study which utilizes tolfenamic acid in combination with gemcitabine and radiation in patients with locally advanced or metastatic pancreatic malignancies which require definitive or palliative radiation.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have a variety of anti-neoplastic mechanisms, including inhibition of cell growth, promotion of apoptosis and inhibition of angiogenesis. Tolfenamic acid is an oral (NSAID) migraine medication which has demonstrated anti-tumor activity in preclinical pancreatic models when used with Gem/XRT (gemcitabine and radiation therapy) and as a single agent.

Each patient enrolled will receive tolfenamic acid in combination with Gem/XRT. Depending on cohort assignment, patients will self-administer tolfenamic acid at either 200mg, 400mg, 600mg or 800mg three times per day. Gemcitabine will be administered intravenously at 400 mg/m2, every seven days for a maximum of 5 doses, starting with the second week of tolfenamic acid administration. Radiation will be given 5 days per week (Monday-Friday) for up to 5 ½ weeks for a maximum dose of 50.4 Gy, beginning with the second week of tolfenamic acid administration.

A maximum of 24 patients will be enrolled in the dose escalation portion of the study. After the maximum tolerated dose (MTD) of tolfenamic acid has been determined, patients will be enrolled in an expansion cohort (at the MTD or the highest dose level achieved if the MTD is not reached) to further assess safety and the anti-tumor response to treatment with tolfenamic acid plus Gem/XRT.

Eligibility Criteria:
Primary Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed:

   1. Locally advanced (potentially resectable) pancreatic adenocarcinoma requiring neoadjuvant radiation or
   2. Locally advanced (nonresectable) or metastatic pancreatic adenocarcinoma requiring definitive or palliative radiation therapy
2. Patients may have either measurable or non-measurable disease (according to RECIST criteria, Version 1.1).
3. Age ≥ 18 years
4. ECOG performance status of 0 or 1.
5. A life expectancy of at least 12 weeks.
6. No other concurrent radiotherapy, chemotherapy or immunotherapy.
7. A minimum of 4 weeks must have elapsed since completion of any prior chemotherapy or immunotherapy.
8. Patient must have:

   1. Absolute neutrophil count (ANC) ≥1,000/mm3
   2. Platelets ≥100,000/mm3
   3. Hemoglobin ≥10 g/dL \[Transfusion to meet the hemoglobin requirement is acceptable\]
   4. Serum creatinine ≤ 1.5 X ULN
   5. Total bilirubin ≤ 1.5 X ULN
   6. Aspartate aminotransferase (AST) ≤ 2.5 X ULN
   7. Alanine aminotransferase (ALT) ≤ 2.5 X ULN
   8. Alkaline phosphatase ≤ 2.5 X ULN
   9. PT/INR ≤ 1.5 X ULN
   10. aPTT ≤ 1.5 X ULN
   11. Urine Protein ≤ Grade 1
9. For patients on warfarin: Must have maintained a stable INR on a stable dose of warfarin for at least 4 weeks prior to start of treatment.

Primary Exclusion Criteria:

1. Patients who have received prior radiation for their current malignancy at the location of interest.
2. Patients who have not recovered (to Grade 1 or less) from adverse events, other than alopecia and neuropathy, caused by previously administered chemotherapeutic agents, at the discretion of the PI/treating physician.
3. Tolfenamic acid use concurrent with, or within 8 weeks prior to the diagnosis of pancreatic cancer.
4. Current use of any non-steroidal anti-inflammatory agents (NSAIDs), including aspirin, (other than tolfenamic acid) within 4 weeks prior to the start of active treatment.
5. Previous history of hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs.
6. History of recurrent peptic ulcer/hemorrhage (two or more distinct episodes).
7. History of gastrointestinal bleeding or perforation related to previous use of NSAIDS.
8. New York Heart Association Functional Classification of 3 or 4.
9. Known autoimmune disease that could preclude the use of radiation, at the discretion of the treating physician.
10. History or evidence of CNS disease (e.g., any brain metastases, primary brain tumor, seizures not controlled with standard medical therapy, or history of stroke).
11. Known HIV positive.
12. Active systemic infection requiring parenteral antibiotic therapy.
13. Receiving systemic steroid therapy. (Inhaled steroid therapy is allowable.)
14. History of other malignancies within the last 5 years with the exception of non- melanoma skin cancer or cervical cancer in situ that has been successfully treated.