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| ID | Type | Description | Link |
|---|---|---|---|
| R21CA123881 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| University of Alabama at Birmingham | OTHER |
| University of North Carolina | OTHER |
| Washington University School of Medicine | OTHER |
| National Cancer Institute (NCI) |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oxaliplatin/Leucovorin/5-FU | Experimental | "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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 5-fluorouracil | Drug |
|
| |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate (ORR) |
| 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival | 4 years | |
| Progression-free Survival (PFS) | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Albert C. Lockhart, M.D. | Washington University School of Medicine | Principal Investigator |
| Laura Goff, M.D. | Vanderbilt University Medical Center | Principal Investigator |
| Richard Goldberg, M.D. | University of North Carolina | Principal Investigator |
| James Posey, M.D. | University of Alabama at Birmingham | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35294 | United States | ||
| Washington University School of Medicine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25232828 | Derived | 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. |
| Label | URL |
|---|---|
| Vanderbilt-Ingram Cancer Center | View source |
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This study opened to participant enrollment in June 2008 and closed to participant enrollment in October 2010.
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| ID | Title | Description |
|---|---|---|
| FG000 | Oxaliplatin/Leucovorin/5-FU | "Good risk" patients with the TSER*2/*2 or *2/*3 genotype or low TS expression genotype Chemotherapy: 5-FU, leucovorin and oxaliplatin (FOLFOX) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Overall Response Rate (ORR) |
| Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia (total WBC) | Investigations | CTCAE (3.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| A. Craig Lockhart, M.D. | Washington University School of Medicine | 314-362-5740 | alockhar@dom.wustl.edu |
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| ID | Term |
|---|---|
| D013274 | Stomach Neoplasms |
| D004938 | Esophageal Neoplasms |
| D009362 | Neoplasm Metastasis |
| ID | Term |
|---|---|
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D005472 | Fluorouracil |
| D000077150 | Oxaliplatin |
| D002955 | Leucovorin |
| ID | Term |
|---|---|
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| NIH |
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| Oxaliplatin |
| Drug |
|
|
| Leucovorin | Drug |
|
|
| 4 years |
| Disease Control Rate (DCR) | DCR - complete response, partial response, and stable disease
| 2 years |
| Tumor Specific Changes That May Alter Treatment Outcomes | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had a partial tumor response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had a partial tumor response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had a partial tumor response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had a partial response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had a partial response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had a partial response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had a partial response. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had stable disease. | 4 years |
| Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had stable disease. | 4 years |
| St Louis |
| Missouri |
| 63110 |
| United States |
| University of North Carolina | Chapel Hill | North Carolina | 27599 | United States |
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine | View source |
| UNC Lineberger Comprehensive Cancer Center | View source |
| University of Alabama at Birmingham . Comprehensive Cancer Center | View source |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| TSER genotypes | Number | participants |
|
| ECOG Performance Status | 0 Fully active, able to carry on all pre-disease performance without restriction
| Number | participants |
|
| Primary tumor type | Number | participants |
|
| Incidence of prior neoadjuvant or adjuvant therapy (>6 months) | Number | percentage of participants |
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Secondary | Overall Survival | Posted | Median | 95% Confidence Interval | months | 4 years |
|
|
|
| Secondary | Progression-free Survival (PFS) | 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 | Posted | Median | 95% Confidence Interval | months | 4 years |
|
|
|
| Secondary | Disease Control Rate (DCR) | DCR - complete response, partial response, and stable disease
| Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
|
|
| Secondary | Tumor Specific Changes That May Alter Treatment Outcomes | This was not completed as the archived tumor samples were not of sufficient quality for DNA extraction or analysis. | Posted | 4 years |
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had a partial tumor response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had a partial tumor response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had a partial tumor response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had a partial response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had a partial response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had a partial response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response) | This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had a partial response. | 9 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G>C (rs34743033) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the ERCC1 c.354C>T (rs11615) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the ERCC2 c.2251A>C (rs13181) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the GSTP1 c.313A>G (rs1695) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the XRCC1 c.1196G>A (rs25487) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| Secondary | Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease) | This outcome looks at what genotypes of the MDR1 c.3435C>T (rs1045642) gene had stable disease. | 11 out of 25 participants had a partial response. | Posted | Number | participants | 4 years |
|
|
|
| 0 |
| 25 |
| 20 |
| 25 |
| Neutropenia | Investigations | CTCAE (3.0) | Systematic Assessment |
|
| Lymphopenia | Investigations | CTCAE (3.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Thrombocytopenia | Investigations | CTCAE (3.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Mucositis/stomatitis | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Taste alteration (dysgeusia) | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Blurred vision | Eye disorders | CTCAE (3.0) | Systematic Assessment |
|
| Allergic reaction/hypersensitivity | Immune system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Hand-foot skin reaction | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Systematic Assessment |
|
| AST, SGOT | Investigations | CTCAE (3.0) | Systematic Assessment |
|
| ALT, SGPT | Investigations | CTCAE (3.0) | Systematic Assessment |
|
| Sensory neuropathy | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (3.0) | Systematic Assessment |
|
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| D004066 |
| Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D013272 | Stomach Diseases |
| D006258 | Head and Neck Neoplasms |
| D004935 | Esophageal Diseases |
| D009385 | Neoplastic Processes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
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