Effects of S-1 and Capecitabine on Coronary Artery Blood Flow

Study Overview
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Brief Summary
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Fluoropyrimidine chemotherapy agents , such as 5-fluorouracil and capecitabine, are occasionally associated with cardiac toxicity. Clinical fluoropyrimidine cardiotoxicity is infrequent, but subclinical toxicity may be much more common. Cardiac toxicity may be less frequent with S-1 as compared with 5-fluorouracil and capecitabine, but head-to-head comparisons are lacking. The purpose of the study is to compare 2 measures of subclinical coronary artery microvascular dysfunction, the coronary flow reserve and the coronary flow response to a cold pressor test, in a patient population who are being treated for adenocarcinoma of the gastrointestinal tract with one of 2 oxaliplatin-containing regimens, either with oxaliplatin plus S-1 or with oxaliplatin plus capecitabine.

Detailed Description
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Patients diagnosed with adenocarcinoma of the gastroesophageal tract are randomly assigned to receive two 3-weekly cycles of either XELOX (intravenous oxaliplatin 130 mg/m2 d.1 followed by oral capecitabine 2000 mg/m2/day divided in 2 daily doses d1-14) or SOX (intravenous oxaliplatin 130 mg/m2 d. 1 followed by oral S-1 25 mg/m2/day BID d1-14). A cross-over between the 2 arms is carried out after the first 2 cycles; patients allocated to XELOX will receive 2 cycles of SOX (cycles 3 and 4), and those allocated to SOX will receive XELOX (cycles 3 and 4). Monitoring of the coronary artery flow, cardiac arrythmias, cardiac symptoms and blood biochemistry is done at baseline, during each chemotherapy cycle (cycles 1 to 4) and after treatment.Study treatment will continue until all patients have discontinued from treatment or maximum 24 weeks from the date of the first day of treatment, whichever occurs first. At that point, treatment may continue at the discretion of the Investigator. Each patient will be followed for survival status for a minimum of 12 months after first dose of study medication. Tumor assessments will be performed throughout the study period and analyzed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1, 2009). Computed tomography (CT) scans will be performed at the end of every 2 cycles. Cardiac assessments will be performed and analyzed using non-invasive transthoracic Doppler echocardiography, 24-h Holter registration, and plasma troponin concentration.

Official Title
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Effects of S-1 and Capecitabine in Combination With Oxaliplatin on the Coronary Artery Blood Flow in Patients Metastatic Gastrointestinal Tract Adenocarcinoma: a Randomized Phase II Study

Conditions
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Esophagus Cancer, Stomach Cancer, Small Bowel Cancer, Colon Cancer, Rectum Cancer

Intervention / Treatment
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* Drug: S-1
* Drug: Capecitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has given written informed consent. Is at least 18 years of age. Has advanced or metastatic gastrointestinal tract adenocarcinoma. No previous cancer chemotherapy for cancer. Measurable or evaluable lesions according to RECIST v1.1 criteria. Is able to take medications orally. Has ECOG performance status 0 or 1. Has a life expectancy of at least 3 months. Has adequate organ function. Exclusion Criteria: Cancer considered operable without prior chemotherapy. Prior chemotherapy to cancer. Previous therapy with fluoropyrimidines or anthracyclines for any indication. Inability to swallow tablets. Known brain metastasis or leptomeningeal metastasis. History of myocardial infarction, coronary stenting/graft. History of unstable angina, coronary/peripheral artery bypass graft. History of cerebrovascular accident or transient ischemic attack. History of pulmonary embolism or deep vein thrombosis. Symptomatic congestive heart failure. Ongoing cardiac dysrhythmias. Patients with any cardiac disease that requires regular medication. Hypertensive crisis or severe hypertension that is not controlled. Is a pregnant or lactating female. The cardiac arterial flow tests cannot be done.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S-1 plus oxaliplatin (SOX)<br>Oxaliplatin 130 mg/m2 d. 1 followed by oral S-1 25 mg/m2/day BID d1-14. | Drug: S-1<br>* S-1 25 mg/m2/day BID d1-14, oxaliplatin injection 130 mg/m2 D1 every 3 weeks<br>* Other names: tegafur/gimeracil/oteracil;Drug: Oxaliplatin<br>* Oxaliplatin 130 mg/m2 D1 every 3 weeks<br>* Other names: Eloxatin;|
| Active Comparator: Oxaliplatin plus capecitabine (XELOX)<br>Intravenous oxaliplatin 130 mg/m2 d.1 followed by oral capecitabine 2000 mg/m2/day divided in 2 daily doses d1-14. | Drug: Capecitabine<br>* capecitabine 2000 mg/m2/day divided in 2 daily doses d1-14, oxaliplatin injection 130 mg/m2 D1 every 3 weeks<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* Oxaliplatin 130 mg/m2 D1 every 3 weeks<br>* Other names: Eloxatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of coronary artery dysfunction | The frequency of subclinical coronary artery dysfunction is as assessed by comparing the coronary flow reserve during chemotherapy with the baseline coronary flow reserve, and the coronary flow response to a cold pressor test. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary artery blood flow rate | The coronary artery blood flow rate is measured with ultrasound. The rates are compared with the baseline and between the groups. | 3 months | 
| Cardiac arrythmias during 24-hour electrocardiogram registration | Cardiac arrythmias detected with Holter cardiac recording. | 3 months | 
| Adverse events between the allocation groups | by CTCAE.4 | 3 months | 
| Response to chemotherapy | by RECIST 1.1 | 3 months | 
| Survival status | Survival from the first dose of study medication to study completion | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fluoropyrimidine, S-1, Teysuno, oxaliplatin, coronary artery flow, coronary artery dysfunction, gastrointestinal tract cancer