Study To Compare Cardiovascular Side Effects Of Teysuno Versus Capecitabine

Study Overview

Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine

Capecitabine is a chemotherapy drug used to treat many types of cancer including bowel and stomach cancer. Unfortunately a side effect of this drug is that it causes heart problems including heart attacks. An alternative drug, called teysuno is used extensively in other countries instead of capecitabine and appears to have less of a bad effect on the heart whilst still killing cancer cells. This study will investigate the effect of these two drugs on the heart and blood vessels and will be the first of its kind in humans.

Fluoropyrimidines (FPs) are widely used chemotherapy agents for the management of patients with colorectal, breast, upper gastrointestinal, head and neck cancers. Capecitabine is an oral prodrug of 5-fluorouracil (5FU) which is used extensively in the UK but is associated with clinically overt cardiotoxicity in up to 9% of patients. Cardiotoxicity occurs more commonly in patients with cardiovascular disease and manifests as chest pain, myocardial infarction, congestive heart failure, or sudden death with a mortality as high as 30%. In a study of continuous ECG Holter monitoring in patients receiving 5FU infusion, the majority (68%) of patients had ischaemic ECG changes and 2 patients died suddenly. We conducted a national survey of UK oncologists and 60% felt that 5FU/capecitabine cardiotoxicity was a significant problem in their clinical practice. Hypotheses for this toxicity include ischaemia secondary to coronary artery spasm, direct endothelial cell toxicity, myocardial toxicity and interactions with the coagulation system. Studies implicate a catabolite of 5FU, in particular fluoro-alanine (FBAL). FBAL is further metabolized to fluoroacetate (FAC), a cardiac toxin that inhibits mitochondrial aconitase, resulting in cell death. Teysuno is an oral fluoropyrimidine that has recently obtained a European licence. It is a combination of tegafur (5-FU prodrug), gimeracil (dihydropyrimidine dehydrogenase (DPD) inhibitor) and oteracil (phosphorylation inhibitor). There have been no reports of cardiac toxicity with teysuno. The incorporation of a DPD inhibitor should reduce FBAL concentrations which may prevent FP cardiotoxicity. However, this remains to be established.

Gastrointestinal Cancer
Cancer of Unknown Primary Site
Pancreatic Cancer
Bile Duct Neoplasms

DRUG: Teysuno
DRUG: Capecitabine

2012-005282-12

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2013-04-29	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-05-11
First Submitted that Met QC Criteria 2013-05-01	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-05-12
First Posted (ACTUAL) 2013-05-03	Results First Posted N/A	Last Verified 2023-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
Double

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Capecitabine single agent Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days	DRUG: Capecitabine
ACTIVE_COMPARATOR: Capecitabine /Oxaliplatin Capecitabine 1000 mg/m2 twice daily, days 1-14 every 21 days (in frail or elderly patients, a CAP dose of 750 mg/m2 BD should be considered). Oxaliplatin will be given as an iv infusion at a dose of 130 mg/m2 over 2-6 hours on day 1.	DRUG: Capecitabine
ACTIVE_COMPARATOR: Teysuno single agent Teysuno will be administered at a dose of 30 mg/m2 twice daily, for 14 days, with a subsequent 7-day rest period. Patients will be assigned a dose on the basis of body surface area (BSA) and will receive one of the following doses twice daily: 40mg (BSA <	DRUG: Teysuno
ACTIVE_COMPARATOR: Teysuno/ Oxaliplatin Teysuno will be administered orally at a dose of 25mg/m2 twice daily, days 1-14 every 21 days Patients will be assigned a dose on the basis of body surface area (BSA) and will receive one of the following doses twice daily: 35mg (BSA < 1.5 m2), 40mg (BSA	DRUG: Teysuno

Primary Outcome Measures	Measure Description	Time Frame
The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment.	This will be recorded using Del Mar Reynolds Lifecard CF/Lifecard 12 recorders, which will record 12 leads over 24 hours and continuously if the storage card is changed daily. Pre-treatment control ECGs will be recorded for 24 hours. Continuous 12-lead monitoring shall be recorded for three days between day 5 and 7 of treatment.	Pre treatment and between day 5-7

Secondary Outcome Measures	Measure Description	Time Frame

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Male or female patients at least 18 years or over with no upper age limit.
Confirmed advanced or metastatic oesophageal, gastric, gastro-oesophageal, small bowel, colorectal, hepatobiliary or pancreatic cancer or cancer of unknown primary.
Suitable for treatment with fluoropyrimidine, either alone or in combination with oxaliplatin.
WHO performance status (PS) 0, 1 or 2 and considered by responsible consultant to be fit to undergo planned chemotherapy and cardiac investigations.
Baseline laboratory tests (within 1 week prior to starting treatment):

Neutrophils >1.5 x109 /L and platelet count > 100 x109 /L
Serum bilirubin <1.5 x upper limit of normal (ULN), alkaline phosphatase <5x ULN, and serum transaminase (either AST or ALT) <3 x ULN
Estimated glomerular filtration rate (eGFR) >30 mL/min (Patients with eGFR 30-50 mL/min will be included but should be treated at a reduced dose (see master prescription chart).
For women of childbearing potential; negative pregnancy test and adequate contraceptive precautions.
Effective contraception for male patients if the risk of conception exists.
Written informed consent for participation in the trial.

Patients who are unfit for the chemotherapy regimens in this protocol, such as:

Known intolerance to CAP or other FPs
Severe uncontrolled concurrent medical illness likely to interfere with protocol treatments
Poorly controlled angina or MI in previous 6 months
Any psychiatric or neurological condition which is felt likely to compromise the patient's ability to give informed consent or to comply with oral medication
Partial or complete bowel obstruction
Pre-existing neuropathy > grade 1 if combination therapy proposed
Patients on therapeutic anticoagulation (warfarin or LMWH).
Patients unable to lie flat.
Patients unable to withstand the visits and cardiovascular investigations proposed within the study.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

NHS Lothian

Investigators

PRINCIPAL_INVESTIGATOR: Sally Clive, MBChB, University of Edinburgh

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

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Resources

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Clinical Trial Record