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

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

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.

Study Overview

• Status: Terminated
• Conditions: Stomach Cancer; Small Bowel Cancer; Colon Cancer; Esophagus Cancer; Rectum Cancer
• Intervention / Treatment: Drug: S-1; Drug: Oxaliplatin; Drug: Capecitabine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Heikki Joensuu
• Investigators: Principal Investigator: Heikki Joensuu, MD, Helsinki University Central Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: August 7, 2014
• First Submitted That Met QC Criteria: August 11, 2014
• First Posted (Estimate): August 13, 2014

Study Record Updates

• Last Update Posted (Actual): August 28, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: oxaliplatin; S-1; Teysuno; fluoropyrimidine; coronary artery flow; coronary artery dysfunction; gastrointestinal tract cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Esophageal Diseases; Colorectal Neoplasms; Stomach Neoplasms; Rectal Neoplasms; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin; Tegafur
• Other Study ID Numbers: HUS-01/2013; 2013-003976-11 (EudraCT Number)