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

Randomized Phase II Trial of 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 2:1 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 38 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 19 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 The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer (CRC)
• Intervention / Treatment: Drug: Regorafenib (BAY 73-4506); Drug: Bevacizumab; Drug: Trifluridine-tipiracil; Drug: 5FU/LV

• Study Type: Interventional
• Enrollment (Estimated): 57
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Safiya Joseph; Phone Number: 3462382420; Email: sdjoseph@houstonmethodist.org
• Study Contact Backup: Name: Titilayo Olubajo; Phone Number: 7133639803; Email: tolubajo@houstonmethodist.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Neal Cancer Center
      • Sub-Investigator: Abdullah Esmail, MD
      • Contact: Maen Abdelrahim, MD, PhD, Pharm B; Phone Number: 713-441-1240; Email: mabdelrahim@houstonmethodist.org
      • Contact: Abdullah Esmail, MD; Email: AEsmail@houstonmethodist.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 0-2.
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:

   a. Total bilirubin ≤ 10 x the upper limits of normal (ULN) b. Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) c. Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) d. Serum creatinine ≤ 1.5 x the ULN e. 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.

   f. 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 ≤70,000 cells/mm3
  3. Hemoglobin ≤9 g/dL
  4. White blood count ≤3000 cells/mm3. 2. Hepatic laboratory values of aspartate transaminase or alanine aminotransferase:
  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 <5.8 g/dL. 4. Total bilirubin >10 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:

  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. 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.

     15. Active or recent (within 3 years) non-colorectal cancer malignancies, except for low-risk, cured cancers (e.g., squamous or basal cell carcinomas, in situ carcinomas, or others deemed non-significant by the investigator).

     16. 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.

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

     18. Ongoing infection > Grade 2 NCI-CTCAE V5.0. 19. Symptomatic metastatic brain or meningeal tumors. 20. The presence of a non-healing wound, non-healing ulcer, or bone fracture. 21. Major surgical procedure or significant traumatic injury within 28 days before start of study medication 22. Renal failure that requires hemo-or peritoneal dialysis.

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

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

     24. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication.

     25. 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.

     26. 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.

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

     28. 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.

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5FU/LV in combination with regorafenib; 5FU/LV will be administered to 38 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.	Drug: Regorafenib (BAY 73-4506); Regorafenib will be administered a starting dose of 80 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 continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.; Drug: 5FU/LV; 5FU/LV administered 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)
Active Comparator: trifluridine-tipiracil (FTD-TPI) plus bevacizumab; an additional 19 patients, will be given as FTD-TPI, administered orally, trice daily, 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.	Drug: Bevacizumab; Bevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15.; Drug: Trifluridine-tipiracil; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of 5FU/LV in combination with regorafenib in metastatic colorectal cancer	Overall survival rate of patients with metastatic colorectal cancer treated with 5FU/LV in combination with regorafenib at 12 months.	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival rate of patients with metastatic colorectal cancer treated with 5FU/LV in combination with regorafenib	Progression-free survival rate of patients with metastatic colorectal cancer treated with 5FU/LV in combination with regorafenib according to RECIST v1.1 criteria.	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 18 months.
Duration of the response of 5FU/LV in combination with regorafenib in third-line metastatic colorectal cancer patients	Duration of the response of 5FU/LV in combination with regorafenib in third-line metastatic colorectal cancer patients from onset of response to progression or death, whichever occurs earlier according to RECIST v1.1 criteria and investigator's tumor assessment.	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 18 months.
Safety and tolerability of 5FU/LV in combination with regorafenib.	To determine the safety and tolerability of 5FU/LV in combination with regorafenib (determined by diseases progression, unacceptable toxicity, and physician's discretion).	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 13 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to treatment failure of 5FU/LV in combination with regorafenib	Time to treatment failure of 5FU/LV in combination with regorafenib (determined by diseases progression, unacceptable toxicity, and physician's discretion).	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 18 months.
Changes in health-related quality of life	Changes in health-related quality of life from baseline to months 6 and 12, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 scores range from 0 to 100. For global health status/quality of life and functional scales (e.g., physical, role, emotional, cognitive, social), higher scores indicate better outcomes (improved quality of life or functioning). For symptom scales/items (e.g., fatigue, pain, nausea/vomiting), higher scores indicate worse outcomes (more severe symptoms).	From baseline to months 6 and 12

Collaborators and Investigators

• Sponsor: The Methodist Hospital Research Institute
• Investigators: Study Director: Abdullah Esmail, MD, Houston Methodist Neal Cancer Center; Principal Investigator: Maen Abdelrahim, MD, PhD, Pharm D, The Methodist Hospital Research Institute

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: March 14, 2025
• First Submitted That Met QC Criteria: March 14, 2025
• First Posted (Actual): March 20, 2025

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Bevacizumab; trifluridine tipiracil drug combination; regorafenib
• Other Study ID Numbers: PRO00038369 (HMCC-GI24-001)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No