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

Phase 2

Completed

Conditions: Stomach Neoplasms
Esophageal Neoplasms

Interventions: Drug: 5-fluorouracil
Drug: Oxaliplatin
Drug: Leucovorin

Registration Number: NCT00515216

Lead Sponsor: Vanderbilt University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Oxaliplatin/Leucovorin/5-FU	5-fluorouracil	"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.
Oxaliplatin/Leucovorin/5-FU	Oxaliplatin	"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.
Oxaliplatin/Leucovorin/5-FU	Leucovorin	"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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	2 years	* 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

Name	Time	Method
Progression-free Survival (PFS)	4 years	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
Tumor Specific Changes That May Alter Treatment Outcomes	4 years
Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)	4 years	This outcome looks at what genotypes of the MDR1 c.3435C\>T (rs1045642) gene had stable disease.
Overall Survival	4 years
Disease Control Rate (DCR)	2 years	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
Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	4 years	This outcome looks at what genotypes of the MDR1 c.3435C\>T (rs1045642) gene had a partial response.

Trial Locations

Locations (4): University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Washington University School of Medicine
🇺🇸
St. Louis, Missouri, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States