Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With Colorectal Cancer

Prior 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 cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors \[Ta (noninvasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)\].
• Discovery of metastases within 6 months after the termination of adjuvant chemotherapy.
• Previous treatment for metastatic disease. Radiotherapy within 28 days prior to first dose of treatment.
• Active cardiac disease including any of the following:
  • Congestive heart failure New York Heart Association (NYHA) class 2, Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), Myocardial infarction less than 6 months before first dose of treatment, Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment.
  • 8;Persistent proteinuria of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 9;Peripheral neuropathy \> grade1 (NCI-CTCAE v5). 10.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of Treatment.
  • 11.Ongoing infection \>grade 2 (NCI-CTCAE v5). 12.Known history of human immunodeficiency virus (HIV) infection. 13.Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required).
  • 14.Seizure disorder requiring medication. 15.Symptomatic metastatic brain or meningeal tumors. 16.Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event ≥ grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of study medication.
  • 17.History of organ allograft. 18.Non-healing wound, ulcer, or bone fracture. 19.Dehydration Grade 1 NCI-CTCAE v5). 20.Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
  • 21.Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products.
  • 22.Interstitial lung disease with ongoing signs and symptoms. 23.Concomitant intake of St. John's wort. 24.Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 3 months after the termination of treatment 25.History of gastrointestinal fistula or perforation 26.Inability to swallow oral medication. 27.Any malabsorption condition. 28.Pregnant or breast-feeding subjects. 29.Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
  • 30.Participation in another clinical study with an investigational product during the last 30 days before inclusion. 31.Patients who might be interconnected with or dependent on the sponsor site or the investigator.
  • 32.Legal incapacity or limited legal capacity.

Other illness

• Uncontrolled hypertension. (Systolic blood pressure \> 140 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management).

Lab values

• ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women Uncontrolled hypertension.

• Written informed consent for full study.
• Documentation of tumor RAS mutation, wild-type homozygous, heterozygous status of UGT1A1 gene. The status of UGT1A1 gene will be performed by the laboratory chosen by the investigator
• Serum uracile \< 16 ng/ml
• Measurable disease, defined as at least one unidimensional measurable lesion on a CT scan, according to RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Life expectancy of at least 3 months.
• Adequate bone marrow, renal and liver functions as evidenced by the following laboratory requirements within 7 days prior to study treatment initiation: Absolute neutrophil count (ANC) ≥ 1,500/ mm3 without biologic response modifiers such as granulocyte colony-stimulating factor (G-CSF), within 21 days before the start of study treatment, Platelet count ≥ 100 000/mm3 , without platelet transfusion within 21 days before the start of study treatment ,Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or erythropoietin, within 21 days before the start of study treatment, Serum creatinine ≤ 1.5 x upper limit of normal(ULN) Serum calcium ≥ Lower limits of normal LLN and ≤ 1.2 x UNL ; Serum magnesium ≥ LLN and ≤ 1.2 x UNL ; Kalemia ≥ LLN, Glomerular filtration rate as assessed by the estimated glomerular filtration rate (eGFR) ≥ 50 mL/min per 1.73 m2 calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated formula, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or bone metastases).
• Lipase ≤ 1.5 x ULN.
• Adequate coagulation, as assessed by the following laboratory test results:
  • International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN, Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, Note: Patients on stable dose (dose has not been changed in at least 28 days) of anticoagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator's discretion. In such case, limits as noted would not apply.
• For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
• For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 4 months following completion of therapy for women and 6 months for male patients. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods of effective contraception. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control.
  • Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Affiliation to the Social Security System.