Sequences Of REGorafenib And Trifluridine/Tipiracil in Patients With Metastatic Colorectal Cancer

Prior treatment

• 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.
• 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).
• Prior treatment with regorafenib or any other tyrosine kinase inhibitor.
• Prior treatment with trifluridine/tipiracil.
• Unresolved toxicity grade >1 (by CTCAE v5.0) caused by prior therapy/procedure, excluding alopecia, hypothyroidism, and oxaliplatin-induced neurotoxicity grade ≤2.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before starting study treatment.
• Chemotherapy within 21 days of starting study treatment.
• Radiotherapy within 4 weeks of starting study treatment, except for palliative radiotherapy within 2 weeks.
• 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).
• Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Any hemorrhage or bleeding event grade ≥3 (CTCAE v5.0) within 4 weeks before starting study treatment.
• Patients unable to swallow oral medications.
• Patients participating in another therapeutic study within the 30 days before enrolment.

Other illness

• Known hypersensitivity to any of the study drugs, study drug classes, or study drug excipients.
• Patient with moderate or severe hepatic impairment (Child-Pugh C).
• Known UGT1A1 polymorphisms. History of Gilbert's syndrome.
• 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.
• Ongoing infection grade 2 (CTCAE v5.0).
• Known history of human immunodeficiency virus (HIV) infection.
• Patients with seizure disorder requiring medication.
• Patients with a history of any bleeding diathesis, irrespective of the severity.
• Presence of a wound, ulcer, or bone fracture that is not healing.
• Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome.
• Presence of gastro-intestinal fistula or perforation.
• Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and their compliance in the study.

Other

• Pregnant or breast feeding women.
• Person deprived of their liberty or under protective custody or guardianship.

• Patients must have provided informed consent before performing any study specific procedures.
• Histological or cytological documented adenocarcinoma of the colon or rectum.
• Patients with metastatic colorectal cancer (stage IV).
• Measurable disease, defined as at least one unidimensional measurable lesion on a computed tomography (CT) scan according to RECIST v1.1.
• 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.
• Patients considered eligible for treatment with both regorafenib and trifluridine-tipiracil.
• Male or female patients aged ≥18 years.
• ECOG performance status of ≤1.
• 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.
• 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.
• Women of childbearing potential must have a negative pregnancy test within 7 days before starting study treatment.
• Patients affiliated to the social security system.
• 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.