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

NCT ID: NCT00515216

Last Updated: 2016-01-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2013-11-30

Brief Summary

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.

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.

Conditions

Stomach Neoplasms; Esophageal Neoplasms

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

5-fluorouracil

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

Leucovorin

Intervention Type: DRUG

Interventions

5-fluorouracil

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

Leucovorin

Intervention Type: DRUG

Other Intervention Names

5-FU; Fluorouracil; Eloxatin; Wellcovorin; citrovorum factor; folinic acid; 5-formyl tetrahydrofolate

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

University of North Carolina

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Craig Lockhart

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Albert C. Lockhart, M.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Laura Goff, M.D.

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Richard Goldberg, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina

James Posey, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

Goff LW, Thakkar N, Du L, Chan E, Tan BR, Cardin DB, McLeod HL, Berlin JD, Zehnbauer B, Fournier C, Picus J, Wang-Gillam A, Lee W, Lockhart AC. Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers. PLoS One. 2014 Sep 18;9(9):e107424. doi: 10.1371/journal.pone.0107424. eCollection 2014.

Reference Type: DERIVED

PMID: 25232828 (View on PubMed)

Related Links

http://www.vicc.org

Vanderbilt-Ingram Cancer Center

http://www.siteman.wustl.edu

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

http://cancer.med.unc.edu

UNC Lineberger Comprehensive Cancer Center

http://www3.ccc.uab.edu

University of Alabama at Birmingham . Comprehensive Cancer Center

Other Identifiers

R21CA123881

Identifier Type: NIH

Identifier Source: secondary_id

View Link

070433

Identifier Type: -

Identifier Source: org_study_id