Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine
关键词
抽象
描述
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.
日期
| 最后验证: | 04/30/2020 |
| 首次提交: | 04/28/2013 |
| 提交的预估入学人数: | 04/30/2013 |
| 首次发布: | 05/02/2013 |
| 上次提交的更新: | 05/10/2020 |
| 最近更新发布: | 05/12/2020 |
| 实际学习开始日期: | 02/04/2014 |
| 预计主要完成日期: | 07/29/2021 |
| 预计完成日期: | 12/29/2021 |
状况或疾病
干预/治疗
Drug: Teysuno
Drug: Capecitabine
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Active Comparator: Capecitabine single agent Capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days | |
| 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. | |
| 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), | |
| 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. |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | 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. |
结果
主要结果指标
1. The primary endpoint of the study will be a difference in the duration of ST deviation pre-treatment and during treatment. [Pre treatment and between day 5-7]
