Clinical trial NCT00515216: Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction (GEJ) Tumors
Official title: Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal (GEJ) Tumors: A Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Stomach Neoplasms
Esophageal Neoplasms
Keywords: Phase II
Gastric cancer
Gastroesophageal cancer
Metastatic
FOLFOX
Thymidylate synthase
Pharmacogenomic
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
Collaborators: name: University of Alabama at Birmingham
name: University of North Carolina
name: Washington University School of Medicine
name: National Cancer Institute (NCI)
First posted: 2007-08-13
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 2 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 4 years
measure: Progression-free Survival (PFS)
timeFrame: 4 years
measure: Disease Control Rate (DCR)
timeFrame: 2 years
measure: Tumor Specific Changes That May Alter Treatment Outcomes
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
measure: Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)
timeFrame: 4 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Washington University School of Medicine
name: Albert C. Lockhart, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Laura Goff, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina
name: Richard Goldberg, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: James Posey, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.