Gemcitabine Plus Pemetrexed Disodium in Treating Patients With Unresectable or Metastatic Biliary Tract or Gallbladder Cancer

OBJECTIVES:

• Determine the maximum tolerated dose of gemcitabine when administered with pemetrexed disodium in patients with unresectable or metastatic biliary tract or gallbladder cancer. (Phase I closed to accrual as of Oct. 2005.)
• Determine the 6-month survival rate of patients treated with this regimen.
• Determine the best objective tumor response rate and duration of best objective tumor response in patients treated with this regimen.
• Determine the time to progression and overall survival of patients treated with this regimen.
• Determine the toxic effects of this regimen in these patients.
• Determine the individual patient variation in toxicity of and/or response to this regimen due to genetic differences in proteins involved in drug response in these patients.

OUTLINE: This is a multicenter phase I dose-escalation study of gemcitabine followed by a phase II study.

• Phase I: Patients receive pemetrexed disodium IV over 10 minutes and gemcitabine IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity (phase I closed to accrual as of October 2005).

Cohorts of 3-6 patients receive escalating doses of gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive pemetrexed disodium as in phase I and gemcitabine at the recommended phase II dose.

Patients are followed every 3 months for 1 year and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 85 patients will be accrued for this study.

• One of the following histologically or cytologically confirmed cancers not amenable to treatment with combined chemotherapy and radiotherapy:

• Biliary tract (intrahepatic, extrahepatic, or ampulla of Vater) carcinoma
• Gallbladder carcinoma
• Unresectable or metastatic disease
• No CNS metastases

• Prior brain metastases treated with surgery or radiosurgery allowed provided treatment was completed at least 4 weeks ago and there is no evidence of CNS progression
• No clinically significant pericardial or pleural effusion or ascites unless able to be drained before study entry
• Performance status - ECOG 0-2
• At least 3 months
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin no greater than 3 times upper limit of normal (ULN)
• AST no greater than 5 times ULN
• Creatinine no greater than 1.5 times ULN
• Creatinine clearance at least 45 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer
• Able to tolerate folic acid, corticosteroids, or cyanocobalamin supplements
• More than 4 weeks since prior biologic or immunologic therapy
• No prior biologic or immunologic therapy for metastatic disease
• No concurrent immunotherapy
• No concurrent colony-stimulating factors during course 1
• No prior chemotherapy for metastatic disease
• No prior gemcitabine
• Prior chemoembolization allowed provided the following are true:

• At least 4 weeks since prior chemoembolization
• Evidence of new tumor growth since therapy
• At least 6 months since prior chemotherapy used as a radiosensitizer (in adjuvant setting or for locally advanced disease)
• No other concurrent chemotherapy
• Prior radiofrequency ablation allowed provided the following are true:

• At least 4 weeks since prior radiofrequency ablation
• Evidence of new tumor growth since therapy
• No prior radiotherapy to 25% or more of the bone marrow
• More than 4 weeks since prior radiotherapy
• No concurrent radiotherapy
• Prior embolization allowed provided the following are true:

• At least 4 weeks since prior embolization
• Evidence of new tumor growth since therapy
• No prior pemetrexed disodium
• No aspirin or nonsteroidal anti-inflammatory drugs for at least 2 days (5 days for long-acting agents [e.g., piroxicam]) before, during, and for at least 2 days after administration of pemetrexed disodium
• No concurrent cyclo-oxygenase-2 inhibitors