| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The study population will consist of male and female patients aged ≥ 18 years old with metastatic colorectal cancer after failure of fluoropyrimidine-, irinotecan-, and oxaliplatin-based chemotherapies, as well as EGFR and VEGF inhibitors in patients eligible for these treatments. |
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| E.1.1.1 | Medical condition in easily understood language |
| metastatic colorectal cancer after failure of fluoropyrimidine-, irinotecan-, and oxaliplatin-based chemotherapies, as well as EGFR and VEGF inhibitors in patients eligible for these treatments. |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079136 |
| E.1.2 | Term | Adenocarcinoma of colon metastatic |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
| The primary objective will be to compare the feasibility of the treatment sequences, regorafenib then trifluridine/tipiracil (Arm A) and trifluridine/tipiracil then regorafenib (Arm B). The feasibility will be assessed in terms of percentage of patients able to receive both line of treatment |
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| E.2.2 | Secondary objectives of the trial |
•The Overall Survival (OS).
•The Progression-Free Survival in the first treatment line (PFS1).
•The Progression-Free Survival in the second treatment line (PFS2).
•The Disease control rate (DCR).
•The Objective response rate (ORR).
•The Time-to-treatment failure in the first treatment line (TTF1).
•The Time-to-treatment failure in the second treatment line (TTF2)
•The quality of life using patient reported outcomes: QLQ-C30 version 3.0
•The time to deterioration of ECOG PS ≥2
•The tolerance of the treatment sequences (by computing the incidence of adverse events using CTCAE v5.0).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients must have provided informed consent before performing any study specific procedures.
2.Histological or cytological documented adenocarcinoma of the colon or rectum.
3.Patients with metastatic colorectal cancer (stage IV).
4.Measurable disease, defined as at least one unidimensional measurable lesion on a computed tomography (CT) scan according to RECIST v1.1
5.The patient must have progressed following exposure of all the following agents: one fluoropyrimidine-based chemotherapy (capecitabine or fluorouracil [5-FU]), combined with oxaliplatin and/or irinotecan (including FOLFOX, FOLFIRI or FOLFOXIRI) as well as EGFR and/or VEGF inhibitors in patients eligible for these treatments.
6.Patients considered eligible for treatment with both regorafenib and trifluridine-tipiracil.
7.Male or female patients aged ≥18 years.
8.ECOG performance status of ≤1.
9.Adequate bone marrow, liver and renal functions as assessed by the following laboratory requirements:
• Total bilirubin ≤1.5 x upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for patients with liver metastasis).
• Alkaline phosphatase limit ≤2.5 x ULN (≤5 x ULN for patients with liver metastasis).
• Serum creatinine ≤1.5 x ULN.
• International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1.5 x ULN. Patients receiving anticoagulants, such as warfarin or heparin are eligible if there is no prior evidence of an underlying abnormality with coagulation.
• Platelet count ≥75000 /mm3, hemoglobin (Hb) ≥9 g/dL, absolute neutrophil count (ANC) ≥1500/mm3. Blood transfusions to meet this inclusion criterion are not allowed.
10.Women of childbearing potential and men must agree to use a highly effective contraception (<1% failure rate) from the signing of the informed consent form until at least 6 months after the last study drug administration. Women using hormonal contraceptive must also use a barrier method.
11.Women of childbearing potential must have a negative pregnancy test within 7 days before starting study treatment.
12.Patients affiliated to the social security system
13.Patient willing and able to comply with the protocol for the duration of the study including treatment, scheduled visits, and examinations throughout the study, including follow up.
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| E.4 | Principal exclusion criteria |
1.Patients with symptomatic brain or meningeal metastasis, unless definitive therapy occurred more than 6 months ago and with a confirmation of tumoral control within 4 weeks of starting study treatment.
2.Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion, except for curatively treated in situ cervical cancer, non-melanoma skin cancer, and superficial bladder tumors: staged Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor with lamina propria invasion).
3.Prior treatment with regorafenib or any other tyrosine kinase inhibitor.
4.Prior treatment with trifluridine/tipiracil.
5.Known hypersensitivity to any of the study drugs, study drug classes, or study drug excipients.
6.Unresolved toxicity grade >1 (by CTCAE v5.0) caused by prior therapy/procedure, excluding alopecia, hypothyroidism, and oxaliplatin-induced neurotoxicity grade ≤2.
7.Patient with moderate or severe hepatic impairment (Child-Pugh C).
8.Known UGT1A1 polymorphisms. History of Gilbert's syndrome.
9.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before starting study treatment.
10.Chemotherapy within 21 days of starting study treatment.
11.Radiotherapy within 4 weeks of starting study treatment, except for palliative radiotherapy within 2 weeks.
12.Active cardiac disease including any of the following:
•Congestive heart failure: New York Heart Association (NYHA) class ≥2.
•Unstable angina (angina symptoms at rest), or a new-onset angina (within the 3 months before enrolment).
•Myocardial infarction that occurred less than 6 months before enrolment.
•Cardiac arrhythmias requiring anti-arrhythmic therapy (treatment with beta blockers or digoxin are permitted)
•Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite treatment).
13.Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months of starting study treatment.
14.Ongoing infection grade >2 (CTCAE v5.0).
15.Known history of human immunodeficiency virus (HIV) infection.
16.Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
17.Patients with seizure disorder requiring medication.
18.Patients with a history of any bleeding diathesis, irrespective of the severity.
19.Any hemorrhage or bleeding event grade ≥3 (CTCAE v5.0) within the 4 weeks before starting study treatment.
20.Presence of a wound, ulcer, or bone fracture that is not healing.
21.Patients unable to swallow oral medications.
22.Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome,
23.Presence of gastro-intestinal fistula or perforation
24.Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and their compliance in the study.
25.Patients participating in another therapeutic study within the 30 days before enrolment.
26.Pregnant or breast feeding women.
27.Person deprived of their liberty or under protective custody or guardianship. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the feasibility of the treatment sequence defined as the percentage of subjects who receive at least two cycles of both regorafenib and trifluridine/tipiracil in each arm. Subjects will be considered as a sucess if they are administered at least two cycles of each line of therapy, i.e. percentage of patients being treated until the first tumor evaluation. |
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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) |
•Overall Survival (OS) is defined as the time interval from randomization until death from any cause.
•Progression-free survival 1 (PFS1) is defined as the time interval from randomization until death or the disease progression observed in the first sequence of treatment in each arm, evaluated using RECIST v1.1.
•Progression-free survival 2 (PFS2) is defined as the time interval from randomization until death or the disease progression is observed in the later sequence of treatment in each arm, evaluated using RECIST v1.1.
•Disease control rate (DCR) is defined as percentage of patients with a best response that is not progressive disease (PD) (either complete response [CR], partial response [PR], or stable disease [SD]) during treatment. DCR will be assessed in each study arm
•Objective response rate (ORR) is defined as percentage of patients with a best response being either complete response [CR] or partial response [PR] during treatment. ORR will be assessed in each study arm.
•Time-to-treatment failure 1 (TTF1) is defined as the time from randomization to treatment discontinuation for any reason (including disease progression, treatment toxicity, patient preference, or death) during the first sequence of treatment in each arm.
•Time-to-treatment failure 2 (TTF2) is defined as the time from randomization to treatment discontinuation for any reason (including disease progression, treatment toxicity, patient preference, or death) during the second sequence of treatment in each arm.
•Quality of life data using the patient reported outcomes, QLQ-C30 version 3.0 will be collected during the study.
•The time to ECOG PS ≥2 deterioration is defined as the time interval between randomization and the first documented ECOG PS ≥2 during the study.
•Data concerning adverse events graded using the CTCAE v5.0 will be collected during the study.
These endpoints will be compared between the study arms.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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