Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction (GEJ) Tumors

This study has been completed.
Sponsor:
Collaborators:
University of Alabama at Birmingham
University of North Carolina
Washington University School of Medicine
Information provided by (Responsible Party):
Craig Lockhart, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00515216
First received: August 9, 2007
Last updated: March 27, 2015
Last verified: March 2015
  Purpose

This study is for patients who have stomach cancer or cancer of the lower part of the esophagus that has spread to other organs. There are many different chemotherapy treatments for this type of cancer. At the present time, there is no general agreement on the way to choose the most beneficial therapy for an individual patient. Patients with different genetic backgrounds may respond differently to the same chemotherapy treatments. In this study the investigators will use a certain genetic difference in an important gene (thymidylate synthase or TS gene) to see whether treating patients who have a particular type of that gene will respond better to a standard chemotherapy regimen. The investigators are hoping that by treating patients according to their genes, that they may respond to treatment of their cancer better and it will help the investigators choose cancer treatments better in the future.


Condition Intervention Phase
Stomach Neoplasms
Esophageal Neoplasms
Drug: 5-fluorouracil
Drug: Oxaliplatin
Drug: Leucovorin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal (GEJ) Tumors: A Phase II Study

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Overall Response Rate (ORR) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    • ORR = complete response + partial response
    • Complete response - disappearance of all target and non-target lesions
    • Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • Progression-free Survival (PFS) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Progressive disease - at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

  • Disease Control Rate (DCR) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    DCR - complete response, partial response, and stable disease

    • Complete response - disappearance of all target and non-target lesions
    • Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter
    • Stable disease - neither sufficient shrinkage to qualify for partial response not sufficient increase to qualify for progressive disease

  • Tumor Specific Changes That May Alter Treatment Outcomes [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had a partial tumor response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had a partial tumor response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had a partial tumor response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had a partial response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had a partial response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had a partial response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had a partial response.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had stable disease.

  • Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had stable disease.


Enrollment: 26
Study Start Date: August 2007
Study Completion Date: November 2013
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Oxaliplatin/Leucovorin/5-FU
"Good risk" patients with the TSER*2/*2 or *2/*3 genotype or low TS expression genotype received treatment of oxaliplatin, leucovorin given over 2 hours along with 5-FU given as intravenous push followed by 5-FU given as intravenous infusion of 46 hours. This treatment was repeated every 2 weeks.
Drug: 5-fluorouracil
Other Names:
  • 5-FU
  • Fluorouracil
Drug: Oxaliplatin
Other Name: Eloxatin
Drug: Leucovorin
Other Names:
  • Wellcovorin
  • citrovorum factor
  • folinic acid
  • 5-formyl tetrahydrofolate

Detailed Description:

Gastric and gastroesophageal junction (GEJ) cancers are a leading cause of cancer mortality. Despite the development of newer chemotherapies, the response rates and median survival in patients with these tumors has remained essentially stagnant. Defining host and molecular/biologic tumor characteristics to customize treatment may lead to improved survival outcomes. Retrospective studies have identified genetic markers that predict treatment outcome. However, there have been no prospective studies in gastric and GEJ cancer evaluating the clinical utility of these genetic factors. We hypothesize that genomically based treatment will improve the expected response rate in patients with gastric and GEJ cancers. We propose a prospective, multi-institutional Phase II clinical trial testing a germline polymorphism in the thymidylate synthase (TS) gene, the number of tandem repeats in the TS enhancer region (TSER) as a treatment selection marker. The polymorphic variant conferring three tandem repeats (TSER*3) has been associated with 5-FU resistance due to high tumor TS expression in comparison to the TSER*2 variant (two tandem repeats). The TSER*3 polymorphism is common (allelic frequency of 0.5-0.8). In the proposed study, we will prospectively genotype patients with gastric and GEJ cancers. Patients who are expected to be 5-FU sensitive (carrying a TSER*2 allele) will receive a 5-FU containing regimen (5-FU, leucovorin, oxaliplatin). Patients who are expected to be 5-FU resistant (homozygous for TSER*3) will not be included in the study. In completing this study, we will determine whether treatment selection based on germline TSER polymorphism status improves the response rate in patients with metastatic gastric and GEJ tumors. Additional correlative studies are proposed to identify confounding factors that may alter the expected outcomes of this treatment approach.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal junction.
  • Patients must have measurable disease.
  • No prior therapy for metastatic disease. Prior neo-adjuvant or adjuvant therapy is permitted if the disease free interval has been longer than 6 months.
  • Age ≥18 years.
  • Life expectancy of greater than 3 months.
  • ECOG (Eastern Cooperative Oncology Group) performance status greater than 2 (Karnofsky greater than 60%).
  • Patients must have normal organ and marrow function.
  • Not pregnant. Not breast feeding.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients may not be receiving any other chemotherapy agents.
  • Patients with known active brain metastases. Patients with treated brain metastases are permitted if stable off steroids for at least 30 days.
  • History of allergic reactions to 5-FU or oxaliplatin.
  • Uncontrolled intercurrent illness.
  • Patients with immune deficiency.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00515216

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
University of Alabama at Birmingham
University of North Carolina
Washington University School of Medicine
Investigators
Principal Investigator: Albert C. Lockhart, M.D. Washington University School of Medicine
Principal Investigator: Laura Goff, M.D. Vanderbilt University
Principal Investigator: Richard Goldberg, M.D. University of North Carolina
Principal Investigator: James Posey, M.D. University of Alabama at Birmingham
  More Information

Additional Information:
No publications provided by Vanderbilt University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Craig Lockhart, Associate Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00515216     History of Changes
Other Study ID Numbers: 070433, R21CA123881
Study First Received: August 9, 2007
Results First Received: February 11, 2015
Last Updated: March 27, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Phase II
Gastric cancer
Gastroesophageal cancer
Metastatic
FOLFOX
Thymidylate synthase
Pharmacogenomic

Additional relevant MeSH terms:
Esophageal Neoplasms
Neoplasms
Stomach Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Esophageal Diseases
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Stomach Diseases
Fluorouracil
Formyltetrahydrofolates
Levoleucovorin
Oxaliplatin
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Growth Substances
Immunologic Factors
Immunosuppressive Agents
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on July 30, 2015