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

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:

1. 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.
2. Deletion of leucovorin infusion and 5FU bolus injection will lessen myelosuppression, mucositis and diarrhea.
3. 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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer; Biliary Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: Cisplatin; Drug: 5-FU

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gemcitabine, 5-FU and Cisplatin; 4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity	Drug: Gemcitabine; Drug: Cisplatin; Drug: 5-FU; Other Names: 5-Fluorouracil

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Colucci et al., 2002, Louvet et al., 2005, Berlin et al., 2002, Cunningham et al., 2009, Heinemann et al., 2008, Valle et al., 2010

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: July 24, 2012
• First Submitted That Met QC Criteria: August 6, 2012
• First Posted (Estimate): August 9, 2012

Study Record Updates

• Last Update Posted (Estimate): October 19, 2016
• Last Update Submitted That Met QC Criteria: September 1, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Gemcitabine, Infusional 5-Fluorouracil,Cisplatin; Advanced Pancreatic and Biliary Cancers; untreated & previously treated pancreatic & biliary cancer.
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Biliary Tract Diseases; Biliary Tract Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Cisplatin; Fluorouracil
• Other Study ID Numbers: UMCC 2011.036; HUM 49518 (Other Identifier: University of Michigan IRBMED)