A Trial of Gemcitabine, Infusional 5-Fluorouracil and Cisplatin for Advanced Pancreatic and Biliary Cancers

Study Overview
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Brief Summary
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Multi-agent chemotherapy has value for patients with advanced pancreatic-biliary cancers leading to responses in a substantial minority and increasing survival. The use of the FOLFIRINOX regimen is limited by its' intensity and toxicity. Previous protocol and clinical experience within the University of Michigan Pancreatic Program leads to an expectation of tolerance and efficacy of the proposed regimen. Advantages of the proposed regimen relative to FOLFIRINOX include: Substitution of gemcitabine for irinotecan. Single agent activity of gemcitabine is at least as good as irinotecan (probably better, especially when delivered by FDR [fixed-dose rate] infusion) and gemcitabine is much better tolerated with less diarrhea, nausea/emesis, myelosuppression and alopecia. Deletion of leucovorin infusion and 5FU bolus injection will lessen myelosuppression, mucositis and diarrhea. Substitution of cisplatin for oxaliplatin will reduce cost of therapy and avoid cold aggravated dysesthesia. Presuming evidence of efficacy and confirmation of tolerance with the proposed regimen, the investigators believe this treatment may be more widely applicable to pancreatic-biliary cancer patients, including those with advanced disease as well as being considered for use in locally advanced and neo- and adjuvant settings.

Detailed Description
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Gemcitabine combined with 5FU may enhance the activity of 5-FU in vivo. Gemcitabine is an inhibitor of ribonucleotide reductase, an enzyme needed for synthesis of deoxynucleotides, and 5-FU interferes with dTTP synthesis by inhibition of thymidylate synthase (TS). It is likely that concomitant administration of gemcitabine and 5FU results in increased cytotoxicity by reducing intracellular dTTP thru two different mechanisms, thereby inhibiting DNA replication and repair. Platinum compounds lead to cell death by forming DNA adducts and causing double strand breaks. By inhibiting DNA synthesis and repair, both gemcitabine and 5-FU potentiate the activity of cisplatin. These interactions underlie the clinical synergism that has been observed with platinum/5FU and platinum/gemcitabine combinations.

Official Title
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A Trial of Gemcitabine, Infusional 5-Fluorouracil and Cisplatin for Advanced Pancreatic and Biliary Cancers

Conditions
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Pancreatic Cancer, Biliary Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: 5-FU
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologic or cytologic diagnosis of pancreatic adenocarcinoma or biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder carcinoma). Patients must have clinical/radiologic evidence of metastatic disease. Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin. Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents. ECOG (Eastern Cooperative Oncology Group) performance status < 1 (A measure of quality of life where 0 represents asymptomatic and 5 represents death). Patients must have adequate bone marrow (absolute neutrophil count >1,500/mm3, platelet count >100,000/mm3) and renal function (serum creatinine < 1.25 x ULN). Patients must have at least one measurable lesion per RECIST criteria. Patients must be free of serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy. Previous malignancies are permitted provided that they have been treated with curative intent and patient is without evidence of active systemic disease. Patients must be informed of the investigational nature of this study and provide written informed consent prior to receiving protocol treatment. Exclusion Criteria: Patients with pre-existing peripheral neuropathy > grade 2 are ineligible. Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin. Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents. Serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy.

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: Gemcitabine, 5-FU and Cisplatin<br>4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity | Drug: Gemcitabine<br> <br> Drug: 5-FU<br> <br> * Other names: 5-Fluorouracil;Drug: Cisplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Untreated and Previously Treated Patients That Had a Partial Response to Treatment | The primary objective of this clinical trial is to estimate the response rate to treatment with the triplet chemotherapy regimen of gemcitabine, infusional 5-FU, and cisplatin, in untreated and previously treated advanced pancreatic and biliary cancer patients. Partial Response (PR) is defined as At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival of Previously Treated and Previously Untreated Patients | To assess the overall survival following treatment with gemcitabine, 5-FU and cisplatin. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gemcitabine, Infusional 5-Fluorouracil,Cisplatin, Advanced Pancreatic and Biliary Cancers, untreated & previously treated pancreatic & biliary cancer.