Clinical trial NCT01845337: Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine
Official title: Toxicity OF Fluoropyrimidines: A Comparative Study of the Cardiotoxicity of capEcitabine and tEysuno
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gastrointestinal Cancer
Cancer of Unknown Primary Site
Pancreatic Cancer
Bile Duct Neoplasms
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: NHS Lothian
First posted: 2013-05-03
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment.
timeFrame: Pre treatment and between day 5-7
Secondary outcomes:
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Edinburgh Cancer Centre
state: Scotland
Study officials:
affiliation: University of Edinburgh
name: Sally Clive, MBChB
role: PRINCIPAL_INVESTIGATOR
References: