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

This study is currently recruiting participants.

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Contacts and Locations

Verified June 2017 by University of Edinburgh

Sponsor:

ClinicalTrials.gov Identifier:

NCT01845337

First Posted: May 3, 2013

Last Update Posted: June 7, 2017

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

Collaborator:

NHS Lothian

Information provided by (Responsible Party):

University of Edinburgh

Purpose

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.

Condition	Intervention	Phase
Gastrointestinal Cancer Cancer of Unknown Primary Site Pancreatic Cancer Bile Duct Neoplasms	Drug: Teysuno Drug: Capecitabine	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double (Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Toxicity OF Fluoropyrimidines: A Comparative Study of the Cardiotoxicity of capEcitabine and tEysuno

Resource links provided by NLM:

Drug Information available for: Capecitabine

U.S. FDA Resources

Further study details as provided by University of Edinburgh:

Primary Outcome Measures:

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.


Estimated Enrollment:	60
Actual Study Start Date:	February 5, 2014
Estimated Study Completion Date:	December 31, 2018
Estimated Primary Completion Date:	December 31, 2018 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Capecitabine single agent Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days	Drug: Capecitabine Other Name: 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 Name: 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 Name: 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 Name: Tegafur / Gimeracil / Oteracil

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.

Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 100 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01845337

Contacts


Contact: Sally Clive, MBChB MD	0131 537 2263 ext 32263	sallyclive@nhslothian.scot.nhs.uk
Contact: Alan Christie, MBChB	0131 537 1925 ext 31925	Alan.Christie@nhslothian.scot.nhs.uk

Locations


United Kingdom
Edinburgh Cancer Centre	Recruiting
Edinburgh, Scotland, United Kingdom, EH4 2XU
Contact: Sally Clive, MBChB 0131 777 350
Principal Investigator: Sally Clive, MBChB MD
Sub-Investigator: Alan Christie, MBChB

Sponsors and Collaborators

University of Edinburgh

NHS Lothian

Investigators


Principal Investigator:	Sally Clive, MBChB	University of Edinburgh

More Information


Responsible Party:	University of Edinburgh
ClinicalTrials.gov Identifier:	NCT01845337 History of Changes
Other Study ID Numbers:	2012-005282-12
First Submitted:	April 29, 2013
First Posted:	May 3, 2013
Last Update Posted:	June 7, 2017
Last Verified:	June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Additional relevant MeSH terms:


Pancreatic Neoplasms Gastrointestinal Neoplasms Bile Duct Neoplasms Neoplasms, Unknown Primary Digestive System Neoplasms Neoplasms by Site Neoplasms Endocrine Gland Neoplasms Digestive System Diseases Pancreatic Diseases Endocrine System Diseases Gastrointestinal Diseases Biliary Tract Neoplasms	Bile Duct Diseases Biliary Tract Diseases Neoplasm Metastasis Neoplastic Processes Pathologic Processes Capecitabine Tegafur Oxaliplatin Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents

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