ADH-1, Gemcitabine Hydrochloride and Cisplatin in Treating Patients With Locally Advanced or Metastatic Pancreatic or Biliary Tract Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the toxicities and determine the recommended dose of ADH-1 given twice weekly
for 3 weeks in combination with cisplatin and fixed-dose rate gemcitabine (gemcitabine
hydrochloride) given on weeks 1 and 2 of the 3 week schedule for 3 cycles in patients with
locally advanced or metastatic pancreatic or biliary tract adenocarcinomas.

SECONDARY OBJECTIVES:

I. To evaluate changes in the levels of intercellular adhesion molecule 1 (ICAM-1),
E-selectin, vascular endothelial growth factor (VEGF), soluble vascular endothelial growth
factor receptor (VEGFR) and basic fibroblast growth factor (B-FGF) during therapy with ADH-1,
cisplatin and gemcitabine.

II. Radiographic assessment of disease status after 3 cycles of chemotherapy with ADH-1,
cisplatin and gemcitabine.

III. To evaluate progression-free and overall survival of patients with locally advanced or
metastatic pancreatic or biliary tract adenocarcinomas treated with ADH-1 given with
cisplatin and fixed dose rate gemcitabine for 3 cycles. Patients with stable or responsive
disease after 3 cycles will continue on maintenance cisplatin and fixed dose rate
gemcitabine.

OUTLINE: This is a dose-escalation study of ADH-1.

Patients receive ADH-1 intravenously (IV) over 20-80 minutes on days 1, 4, 8, 11, 15, and 18,
cisplatin IV and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment
repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable
toxicity. Patients with stable or responsive disease may receive maintenance therapy with
cisplatin and gemcitabine hydrochloride.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have adenocarcinoma of the pancreas or biliary tree (intrahepatic or
extrahepatic cholangiocarcinoma, gallbladder or ampulla of Vater) that is locally
advanced, but non-resectable, metastatic or residual disease after attempted surgical
resection

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 or better

- Absolute neutrophil count (ANC) of 2000 per mcL or higher

- Platelet count of 100,000 per mcL or higher

- Patients must have a serum creatinine that is at or below the upper limits of the
institutional normal range OR a creatinine clearance of 60 mL per min or higher
corrected for body surface area (BSA)

- The total bilirubin must be at or below 2.0 mg/dL in the absence of biliary
obstruction; if the patient has biliary obstruction, biliary decompression will be
required; either endoscopic placement of a biliary stent or percutaneous transhepatic
drainage is acceptable; once biliary drainage has been established, institution of
protocol therapy may proceed when the total bilirubin falls to 3.0 mg/dL or lower

- Patients need not have measurable disease for this study

- The patient must be aware of the neoplastic nature of his/her disease and willingly
provide written, informed consent after being informed of the procedure to be
followed, the experimental nature of the therapy, alternatives, potential benefits,
side-effects, risks, and discomforts

- Women of reproductive potential must be non-pregnant and non-nursing and must agree to
employ an effective barrier method of birth control throughout the study and for up to
6 months following treatment

- Women of child-bearing potential must have a negative pregnancy test within 7 days of
initiating study; (no childbearing potential is defined as age 55 years or older and
no menses for two years or any age with surgical removal of the uterus and/or both
ovaries)

Exclusion Criteria:

- Patients may not have received prior chemotherapy for metastatic adenocarcinoma of the
pancreas or biliary tract; prior adjuvant chemotherapy is acceptable provided that 6
months or longer has elapsed since completion of the prior therapy

- History of allergy to platinum compounds or to antiemetics appropriate for
administration in conjunction with protocol-directed chemotherapy

- Uncontrolled inter-current illness including, but not limited to ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure,
unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might
jeopardize the ability of the patient to receive the chemotherapy program outlined in
this protocol with reasonable safety

- Pregnant and nursing women are excluded from this study

- Patients with prior malignancy will be excluded except for adequately treated basal
cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other
cancers from which the patient has been disease-free for at least 5 years