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. MedDRA version: 20.0 Level: LLT Classification code 10079136 Term: Adenocarcinoma of colon metastatic System Organ Class: 100000004864
Conditions
Interventions
Product Name: Regorafenib
Product Code: L01XE21
Pharmaceutical Form: Tablet
CAS Number: 755037-03-7
Other descriptive name: REGORAFENIB
Concentration unit: mg milligram(s)
Concentration type: equal
Co
Sponsors
UNICANCER
Eligibility
Sex/Gender
All
Inclusion criteria
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 received two or more previous lines of treatment for metastatic disease. The prior treatment lines must include at least one fluoropyrimidine-based chemotherapy 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 =100000 /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 (=65 years) yes F.1.3.1 Number of subjects for this age range 200
Exclusion criteria
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 severe hepatic impairment (Child-Pugh C). 8.Known UGT1A1 and/or UGT1A9 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: •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). ;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.;Timepoint(s) of evaluation of this end point: - | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. ;Timepoint(s) of evaluation of this en | — |
Countries
Belgium, France, Italy
Contacts
Public ContactLaure MONARD
UNICANCER
Outcome results
None listed