Phase II Study of PX-12 in Patients With Advanced Pancreatic Cancer

A Randomized Phase II Open-Label Study of Two Different Dose Levels of PX-12 in Patients With Advanced Carcinoma of the Pancreas Whose Tumors Have Progressed on Gemcitabine or on a Gemcitabine-Containing Combination

This study is being conducted to evaluate the clinical efficacy, biologic activity (inhibition of PX-12 target thioredoxin-1) and effects of an expired metabolite of PX-12 in patients with advanced pancreatic cancer.

In a Phase I trial, PX-12 demonstrated anti-tumor activity and pharmacodynamic activity across a wide dose range. At higher doses, one side effect of the agent was a garlic-like odor of an expired metabolite. This study is being conducted to evaluate the clinical efficacy, biologic activity (inhibition of PX-12 target thioredoxin-1) and effects of the expired metabolite at two dose levels of PX-12. This study will determine if the efficacy and biologic activity achieved at either of the two dose levels is sufficient to proceed to further studies without pushing to the maximally tolerated dose.

Inclusion Criteria:

• Histologically- or cytologically-confirmed diagnosis of advanced carcinoma of the pancreas (stage IV disease only).
• Patients whose tumor has progressed on gemcitabine or on a gemcitabine-containing combination. Patients must have received no more than two prior regimens for metastatic disease. Use of gemcitabine as a radiation sensitizer in combination with radiotherapy for localized disease will not be considered a prior gemcitabine-containing regimen if gemcitabine was received for ≤ 1 month following completion of radiotherapy. In addition, the use of 5-fluorouracil as a radiation sensitizer for localized disease will be allowed and not counted as a prior regimen if the 5-FU was continued for ≤ 1month following completion of radiotherapy.
• Karnofsky Performance Status of ≥ 70%.
• Patients must have discontinued previous anti-cancer therapy or other investigational agent at least three weeks or within 5 half lives of the drug (whichever is shorter) prior to entry into the study (six weeks for mitomycin C or nitrosureas) provided that all toxicities from prior treatment have resolved to a Grade 1 or less.
• Patients must have discontinued radiation therapy at least two weeks prior to entry into the study and have recovered from all radiation-related toxicities.
• Adequate organ function including the following:
• ANC ≥ 1500 cells/microL; platelets > 100,000/microL; hemoglobin ≥ 9 g/dL (may be transfused to this level).
• Bilirubin ≤ 2.0 mg/dL; aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 times institutional upper limit of normal (ULN) OR < 5 times institutional ULN if the subject has documented liver metastases.
• Creatinine ≤2.0 mg/dL.
• CA19-9 level >2 times ULN.
• Disease that is measurable by CT scan per RECIST criteria (Appendix IV).
• PET/CT or PET scan with SUV of ≥ 5.0 in at least one lesion on an 18F FDG scan.

Exclusion Criteria:

• Active infection requiring antibiotics at study entry.
• Any serious concomitant systemic disorder that in the opinion of the investigator would place the patient at excessive or unacceptable risk of toxicity.
• Patients with active (requiring continuous medical therapy) pulmonary disease (COPD, asthma) or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest X-ray or PET/CT scan.
• Significant central nervous system or psychiatric disorder(s) that preclude the ability of the patient to provide informed consent.
• Known or suspected brain metastases that have not received adequate therapy. Patients must be stable without requirement for steroids or seizure medications.
• Major surgery within 4 weeks of study entry.
• Chemotherapy/investigational drugs within 3 weeks or within 5 half lives of the drug (whichever is shorter) of study entry, provided that all toxicities from prior treatment have resolved to a Grade 1 or less.
• Inability to tolerate prophylactic (1 mg/day) coumadin.