Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine (TOFFEE)

Toxicity OF Fluoropyrimidines: A Comparative Study of the Cardiotoxicity of capEcitabine and tEysuno

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer; Gastrointestinal Cancer; Bile Duct Neoplasms; Cancer of Unknown Primary Site
• Intervention / Treatment: Drug: Capecitabine; Drug: Teysuno

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Edinburgh Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

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; Other Names: Xeloda tablets
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; Other Names: Xeloda tablets
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 < 1.5 m2), 45 mg (BSA 1. 5 to < 1.7 m2), 55mg (BSA 1.7 - 1.9 m2),	Drug: Teysuno; Other Names: Tegafur / Gimeracil / Oteracil
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 1.5 to < 1.7 m2), 45mg (BSA 1.7 - 1.9 m2), 50mg (BSA >1.9 m2). Oxaliplatin will be given as an iv infusion at a dose of 130 mg/m2 over 2-6 hours on day 1.	Drug: Teysuno; Other Names: Tegafur / Gimeracil / Oteracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: Sally Clive, MBChB, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2014
• Primary Completion (Actual): March 18, 2020
• Study Completion (Actual): October 8, 2020

Study Registration Dates

• First Submitted: April 29, 2013
• First Submitted That Met QC Criteria: May 1, 2013
• First Posted (Estimate): May 3, 2013

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Neoplastic Processes; Biliary Tract Diseases; Neoplasm Metastasis; Bile Duct Diseases; Biliary Tract Neoplasms; Gastrointestinal Neoplasms; Neoplasms, Unknown Primary; Bile Duct Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Tegafur
• Other Study ID Numbers: 2012-005282-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) will be shared with other researchers on request
• IPD Sharing Time Frame: 1 year after completion of study until 5 years after archiving
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF