5-Fluorouracil/Leucovorin (5FU/LV) in Combination With Regorafenib in Patients With Metastatic Colorectal Cancer

This is a non-inferiority randomized phase II trial investigating the efficacy and safety of 5FU/LV in combination with regorafenib for patients with metastatic colorectal cancer in the third-line setting.

Patients will be randomly assigned in a 1:1 ratio between 5FU/LV combined with regorafenib or trifluridine-tipiracil (FTD-TPI) plus bevacizumab.

Arm 1 (Treatment Arm) will consist of the 5FU/LV administered to 26 patients as (LV \[400 mg/m² IV over 120 minutes\], followed by 5FU \[400 mg/m² IV bolus then 2400 mg/m² IV infusion over 46 hours\] in 2-week cycles) and regorafenib will be administered dose of 80-120 mg per day with weekly 40 mg per day increases to a maximum of 120 mg per day for 3 weeks on /1 week off until disease progression, up to 12 cycles of treatment.

Arm 2 (Control Arm) received by an additional 26 patients, will be given as FTD-TPI, administered orally, BID, at a starting dose of 35 mg/m2 of body-surface area, on days 1 through 5 and on days 8 through 12 every 28 days. Bevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15. The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.


Eligibility Criteria:
Inclusion Criteria:

1. Male or female ≥18 years of age.
2. Histopathological or cytologically confirmed metastatic CRC.
3. Failed second-line therapy for metastatic disease.
4. A minimum of one measurable disease per RECISTv1.1.
5. ECOG performance status of 0 or 1.
6. Life expectancy ≥6 months per treating physician or principal investigator.
7. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.
8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:

   1. Total bilirubin ≤ 1.5 x the upper limits of normal (ULN)
   2. Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
   3. Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
   4. Serum creatinine ≤ 1.5 x the ULN
   5. International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x ULN. (Subjects who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
   6. Platelet count ≥100000 /mm3, hemoglobin (Hb) ≥9 g/dL, absolute neutrophil count (ANC) ≥1500/mm3. Blood transfusion to meet the inclusion criteria will not be allowed.
9. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. The definition of adequate contraception will be based on the judgment of the investigator.
10. Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 2 months after the last dose of study drug as outlined in Appendices 12.2
11. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.
12. Subject must be able to swallow and retain oral medication.

Exclusion Criteria:

* 1. Hematology laboratory values of:

  1. Absolute neutrophil count ≤1000 cells/mm3
  2. Platelets ≤100,000 cells/mm3
  3. Hemoglobin ≤9 g/dL
  4. White blood count ≤3000 cells/mm3. 2. Hepatic laboratory values of aspartate transaminase or alanine aminotransferase:

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  1. \>5 × upper limits of normal (ULN) if the documented history of hepatic metastases; or
  2. \>2.5 × ULN if no liver metastases are present. 3. Serum albumin \<2.8 g/dL. 4. Total bilirubin \>1.5 × ULN or \>1.5 mg/dL. 5. Prothrombin time (PT) or international normalized ratio (INR) \>1.5 × ULN. Note: Patients receiving therapeutic doses of anticoagulant therapy may be considered eligible if PT and INR are within the acceptable institutional therapeutic limits.

     6. Serum creatinine or serum urea \>1.5 × ULN. 7. Estimated glomerular filtration rate \<50 mL/min. 8. Positive pregnancy test, pregnant, or breastfeeding (female patients only). 9. Any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.

     10. Any clinically significant and/or uncontrolled cardiac-related abnormality that would compromise patient safety or the outcome of the study including, but not limited to:

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  1. Arrhythmia
  2. Bradycardia
  3. Tachycardia
  4. Symptomatic valvular disease
  5. Symptomatic congestive heart failure is classified by New York Heart Association as Class III or IV
  6. Unstable angina pectoris. 11. Myocardial infarction within the past 6 months from the consent date. 12. Active bleeding diathesis. 13. Current complaints of persistent constipation or history of chronic constipation, bowel obstruction, or fecaloma within the past 6 months from the consent date.

     14. Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other immunosuppressive agents.

     15. Known history and/or uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2 from the consent date.

     16. History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption.

     17. History of malignancy or active treatment for malignancy (i.e., radiation or chemotherapy, including monoclonal antibodies) within 3 years. Note: Patients with squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or other malignancies that in the opinion of the investigator are considered cured may participate.

     18. Receipt of live, attenuated vaccine (e.g., intranasal influenza, measles, mumps, rubella, varicella) or close contact with someone who has received a live, attenuated vaccine within the past 1 month. Note: Influenza vaccine will be allowed if administered \>21 days.

     19. Receipt of any investigation agent or study treatment within the past 30 days.

     20. Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months.

     21. Ongoing infection \> Grade 2 NCI-CTCAE V5.0. 22. Symptomatic metastatic brain or meningeal tumors. 23. The presence of a non-healing wound, non-healing ulcer, or bone fracture. 24. Major surgical procedure or significant traumatic injury within 28 days before start of study medication 25. Renal failure that requires hemo-or peritoneal dialysis.

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  1. Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter study.

     26. Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \> 90 mm Hg \[NCI-CTCAE V5.0\] on repeated measurement) despite optimal medical management.

     27. Evidence or history of bleeding diathesis or coagulopathy. 28. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication.

     29. Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment within 6 months of informed consent.

     30. Patients with any previously untreated or concurrent cancer that is distinct in primary site or histology except cervical cancer in-situ, treated ductal carcinoma in situ of the breast, curatively treated nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before registration are allowed. All cancer treatments must be completed at least 3 years prior to registration.

     31. Patients with phaeochromocytoma. 32. Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy.

     33. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea).

     34. History of organ allograft (including corneal transplant). 35. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial.

     36. Any malabsorption condition. 37. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.

     38. Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.