Gastrointestinal CancerPhase 2TOFFEENCT01845337
Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine
A Phase 2 study testing Teysuno and Capecitabine in people with Gastrointestinal Cancer and Cancer of Unknown Primary Site, run by University of Edinburgh at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Gastrointestinal Cancer, Cancer of Unknown Primary Site, Pancreatic Cancer
- What is being tested?
- Teysuno and Capecitabine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 5 Feb 2014to 8 Oct 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Edinburgh Cancer Centre
Edinburgh, Scotland, EH4 2XU
About this study
Official title: 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.
Read the 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.
- Conditions
- Gastrointestinal Cancer, Cancer of Unknown Primary Site, Pancreatic Cancer, Bile Duct Neoplasms
- Being tested
- Teysuno, Capecitabine
- Medical subject headings
- Gastrointestinal Neoplasms, Neoplasms, Unknown Primary, Pancreatic Neoplasms, Bile Duct Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TeysunoDrug
Also called Tegafur / Gimeracil / Oteracil
CapecitabineDrug
Also called Xeloda tablets
| Study group | Role | What they receive |
|---|---|---|
| Capecitabine single agent | Active comparator | Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days Receives: Drug: Capecitabine |
| Capecitabine /Oxaliplatin | Active comparator | 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. Receives: Drug: Capecitabine |
| Teysuno single agent | Active comparator | 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), Receives: Drug: Teysuno |
| Teysuno/ Oxaliplatin | Active comparator | 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. Receives: Drug: Teysuno |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Pre treatment and between day 5-7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2013 (estimated)
- Study start5 Feb 2014
- Primary completion18 Mar 2020
- Study completion8 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Gastrointestinal CancerStudies of the same condition, open and under way.
- More trials run by University of EdinburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Edinburgh
- Sponsor type
- University, hospital or other
- Collaborators
- NHS Lothian
- Responsible party
- Sponsor
- Investigators
- Sally Clive, MBChB, Principal investigator, University of Edinburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01845337
- Sponsor's protocol ID
- 2012-005282-12
- Acronym
- TOFFEE
- Status last verified
- May 2023
- First submitted
- 29 Apr 2013
- Last updated
- 12 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) will be shared with other researchers on request
Study at a glance
From the registry record, last updated by the sponsor on 12 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Toxicity OF Fluoropyrimidines: A Comparative Study of the Cardiotoxicity of capEcitabine and tEysuno
- ClinicalTrials.gov ID
- NCT01845337
- Acronym / sponsor ID
- TOFFEE / 2012-005282-12
- Conditions
- Gastrointestinal Cancer, Cancer of Unknown Primary Site, Pancreatic Cancer, Bile Duct Neoplasms
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- University of EdinburghUniversity, hospital or other
- Collaborators
- NHS Lothian
- Study start
- 5 Feb 2014 (actual)
- Primary completion
- 18 Mar 2020 (actual)
- Study completion
- 8 Oct 2020 (actual)
- First posted
- 3 May 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Capecitabine single agent | Active comparator | Drug: CapecitabineCapecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days |
| Capecitabine /Oxaliplatin | Active comparator | Drug: CapecitabineCapecitabine 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 single agent | Active comparator | Drug: TeysunoTeysuno 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/ Oxaliplatin | Active comparator | Drug: TeysunoTeysuno 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. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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):
Key exclusion criteria (10 listed)
- Patients who are unfit for the chemotherapy regimens in this protocol, such as:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TeysunoAlso: Tegafur / Gimeracil / Oteracil | Drug | Teysuno single agent, Teysuno/ Oxaliplatin |
| CapecitabineAlso: Xeloda tablets | Drug | Capecitabine /Oxaliplatin, Capecitabine single agent |
Primary outcome
The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment.
Time frame: Pre treatment and between day 5-7
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 May 2023.
- Individual participant dataSharing planned: Yes. Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) will be shared with other researchers on request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sally Clive, MBChB principal investigator
University of Edinburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Teysuno and Capecitabine in people with Gastrointestinal Cancer and Cancer of Unknown Primary Site, run by University of Edinburgh at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment. (time frame: Pre treatment and between day 5-7). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 May 2023.