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

Primary Purpose

Gastrointestinal Cancer, Cancer of Unknown Primary Site, Pancreatic Cancer

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Teysuno
Capecitabine
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Cancer

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Edinburgh Cancer Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Capecitabine single agent

Capecitabine /Oxaliplatin

Teysuno single agent

Teysuno/ Oxaliplatin

Arm Description

Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days

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.

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),

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
April 29, 2013
Last Updated
May 11, 2023
Sponsor
University of Edinburgh
Collaborators
NHS Lothian
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1. Study Identification

Unique Protocol Identification Number
NCT01845337
Brief Title
Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine
Acronym
TOFFEE
Official Title
Toxicity OF Fluoropyrimidines: A Comparative Study of the Cardiotoxicity of capEcitabine and tEysuno
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
February 5, 2014 (Actual)
Primary Completion Date
March 18, 2020 (Actual)
Study Completion Date
October 8, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
NHS Lothian

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrointestinal Cancer, Cancer of Unknown Primary Site, Pancreatic Cancer, Bile Duct Neoplasms

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
InvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Capecitabine single agent
Arm Type
Active Comparator
Arm Description
Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days
Arm Title
Capecitabine /Oxaliplatin
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Teysuno single agent
Arm Type
Active Comparator
Arm Description
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),
Arm Title
Teysuno/ Oxaliplatin
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Teysuno
Other Intervention Name(s)
Tegafur / Gimeracil / Oteracil
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Other Intervention Name(s)
Xeloda tablets
Primary Outcome Measure Information:
Title
The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment.
Description
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.
Time Frame
Pre treatment and between day 5-7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sally Clive, MBChB
Organizational Affiliation
University of Edinburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Edinburgh Cancer Centre
City
Edinburgh
State/Province
Scotland
ZIP/Postal Code
EH4 2XU
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine

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