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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as gemcitabine work in different ways to stop tumor cells from dividing so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Combining gemcitabine with pemetrexed disodium may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of gemcitabine when given together with pemetrexed disodium to see how well it works in treating patients with unresectable or metastatic biliary tract or gallbladder cancer.

Detailed Description
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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.

Official Title
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Phase I/II Trial Of Gemcitabine And ALIMTA In Patients With Measurable Or Evaluable, Unresectable Or Metastatic Biliary Tract Carcinoma (Intrahepatic, Extrahepatic, Ampulla Or Vater) And Gallbladder Carcinoma

Conditions
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Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Liver Cancer

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: pemetrexed disodium


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pemetrexed + gemcitabine<br>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. | Drug: gemcitabine hydrochloride<br> <br> Drug: pemetrexed disodium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival after 6 months of treatment |  | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response as assessed by RECIST criteria every 8-16 weeks |  | Up to 16 weeks | 
| Toxicity as assessed by CTC v3 every 4 weeks |  | Up to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced adult primary liver cancer, unresectable gallbladder cancer, unresectable extrahepatic bile duct cancer, adult primary cholangiocellular carcinoma