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