E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
colorectal or oesogastric adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
colorectal or oesogastric adenocarcinoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052360 |
E.1.2 | Term | Colorectal adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017758 |
E.1.2 | Term | Gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the rate of cardiovascular events in patients treated with trifluridine/tipiracil +/- oxaliplatin over a 3-month period. Cardiovascular events are defined as follows: - Acute coronary syndrome without ST segment elevation, - Acute coronary syndrome with ST segment elevation, - Acute myocardial infarction, - Heart failure, - Arrhythmia (atrial fibrillation, flutter, junctional tachycardia, ventricular tachycardia), - Cardiovascular death, - Sudden death of any cause.
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety profile of the trifluridine/tipiracil and oxaliplatin combination (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v 5.0), - To evaluate disease control rate (DCR; the proportion of patients who experience a partial response, complete response (CR), or have stable disease as their best response), - To evaluate the 3-month drop-out rate for limiting toxicity. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated informed consent and willingness to comply with all study procedures and availability for the study duration, 2. Histologically confirmed oesogastric, gastric, colon and/or rectum adenocarcinoma, 3. Patients with metastatic non-resectable (oesogastric or colorectal) or adjuvant (colorectal stage III) adenocarcinoma previously treated by fluoropyrimidines (5-FU or capecitabine), 4. Age ≥18 years, 5. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, 6. Patients who presented an episode of cardiac angina-related thoracic pain due to 5-FU or capecitabine (minimum 21 days [3 weeks] between event and inclusion): at least one of the following events: - Instable angina , - Acute coronary syndrome (ACS) without ST-segment elevation nor troponin rise. 7. Contraindication to continue treatment with 5FU or capecitabine confirmed and documented by a cardiologist, 8. Indication to receive trifluridine/tipiracil ± oxaliplatin considered better than absence of therapy (colo-rectal stage III) or the best alternative therapy (metastatic colo-rectal and oeso-gastric or gastric) confirmed by a Multidisciplinary Consultation Meeting, 9. No contraindication to receive trifluridine/tipiracil (related toxicity), 10. No prior treatment with trifluridine/tipiracil, 11. Following laboratory values obtained within 14 days (2 weeks) prior to start of study treatment: * Hematological status: - absolute neutrophil count (ANC) ≥ 1.5 x 109/L; - platelets ≥ 100 x 109/L; - hemoglobin ≥ 9 g/dL, * Adequate renal function: - serum creatinine level < 150 µM - and creatinine clearance ≥ 50 ml/min using the Cockroft-Gault formula, * Adequate liver function: - serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), - alkaline phosphatase (ALP) < 5 x ULN, - aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, 12. For female patients of childbearing potential, negative serum pregnancy test within 7 days (1 week) prior starting the study treatment, 13. Female patients of childbearing potential must commit to using reliable and effective methods of contraception during the trial and until at least 6 months after the end of study treatment. Male patients with a partner of childbearing potential must agree to use effective contraception in addition to the contraceptive method used by their partner during the trial and until at least 6 months after the end of study treatment. 14. Registration in a national health care system (PUMa – Protection Universelle Maladie included).
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E.4 | Principal exclusion criteria |
1. For metastatic colo-rectal-cancer, MSI and/or dMMR tumor 2. For metastatic oeso-gastric and gastric adenocarcinoma, HER+++ or HER++ FISH positive tumor 3. Left ventricular dysfunction with a left ventricular ejection fraction (LVEF) < 35% with or without an automatic implantable defibrillator, 4. Non-revascularized multivessel coronary artery disease 5. ACS with ST elevation, and/ or troponin rise, 6. QT/QTc interval > 470 ms (for women) and > 450 ms (for men), NB: Caution is required when using medicinal products with human thymidine kinase substrates, e.g. zidovudine and other drugs known to prolong the QTc interval ( exhaustive list on https: //www.crediblemeds.org.” 7. Documented coronary vasospasm during 5-FU treatment leading to myocardial infarction, 8. Pregnancy and breastfeeding, 9. Treatment with any other investigational medicinal product within 28 days (4 weeks) before start of the study treatment, 10. Rare hereditary problems of galactose intolerance, the Lapp lactose deficiency, or glucose-galactose malabsorption, 11. Any other serious and uncontrolled non-malignant disease, 12. Major surgery or traumatic injury within 28 days (4 weeks) before the start of study treatment, 13. Patients with known allergy to any excipient to study drugs, 14. Bowel obstruction or inability to swallow tablets, 15. Peripheral neuropathy Grade > 1 for the oxaliplatin schedule, 16.Non resolved non-hematological toxicities from prior therapies (grade >2) 17. Abnormal values at inclusion for : - kalemia ; - Magnesemia; - Calcemia and corrected calcium level 18. Patient under a legal protection regime (guardianship, curatorship or judicial safeguard, or administrative decision or incapable of giving his/her consent 19. Impossibility of submitting to the medical follow-up of the study for geographical, social reasons or psychiatric illness 20. Patients admitted to a health or social establishment for purposes other than that of the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The rate of cardiovascular events at 3 months |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- The incidence of AEs (NCI-CTCAE v5.0) - Disease control rate (DCR) - The 3-month drop-out rate for limiting toxicity
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- AEs : every visit during treatment and until 28 days after the last dose (NCI-CTCAE version 5.0) - until 3 months of the last visit of the last patient - 3 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |