5‑Fluorouracil–based chemotherapy plus fruquintinib for advanced or metastatic colorectal cancer

Phase II Trial of 5-Fluorouracil (5FU)-Based Therapy in Combination With Fruquintinib as First Line in Patients With Locally Advanced Unresectable or Metastatic Colorectal Cancer

This phase II test will combine 5‑FU–based chemotherapy with the oral drug fruquintinib as a first-line treatment for adults with locally advanced unresectable or metastatic colorectal cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: The Methodist Hospital Research Institute (Academic / other)
• Drugs / interventions: chemotherapy, radiation, prednisone, fruquintinib
• Locations: 1 site (Houston, Texas)
• Trial ID: NCT07042685 on ClinicalTrials.gov

What this trial studies

This Phase II, single-arm trial will enroll 50 patients to receive either FOLFIRI or mFOLFOX6 combined with oral fruquintinib in 28-day cycles, with fruquintinib given on days 1–21. The first three patients start at 4 mg daily with subsequent patients potentially dosed at 5 mg if early dose-limiting toxicities are not seen, and doses may be adjusted per investigator. After six months, patients with stable disease or better transition to maintenance 5‑FU plus fruquintinib until progression or discontinuation. The primary endpoint is time to progression by RECIST v1.1, with secondary endpoints including safety, tolerability, and duration of response, conducted across Houston Methodist sites.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed locally advanced unresectable or metastatic colorectal cancer, measurable disease per RECIST v1.1, no prior systemic therapy for metastatic disease, and who are medically fit for FOLFIRI or mFOLFOX6 plus oral therapy.

Not a fit: Patients who have already received systemic treatment for metastatic disease or whose molecular profile indicates a different first-line standard (for example MSI‑high patients who should receive immunotherapy) may not benefit from this regimen.

Why it matters

Potential benefit: If successful, the combination could extend time to progression and provide a more effective first-line option for patients with metastatic colorectal cancer.

How similar studies have performed: Fruquintinib has demonstrated benefit as a later-line therapy in metastatic CRC and other VEGFR inhibitors have shown activity when combined with chemotherapy, but using fruquintinib with 5‑FU–based regimens in the first-line setting is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Male or female ≥18 years of age.
2. Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period.
3. Histopathologically or cytologically confirmed locally advanced unresectable or metastatic colorectal cancer. The study will include an all-comer population, meaning that patients will not be excluded based on specific molecular markers such as microsatellite instability-high (MSI-H) or B-Raf proto-oncogene mutations (BRAF mutations). However, as part of the Standard of Care, comprehensive molecular testing will be performed to assess MSI status, and other relevant biomarkers. For patients with MSI-H or BRAF mutations confirmed, treatment may be adjusted per Standard of Care practices.
4. Measurable disease per RECISTv1.1.
5. No prior systemic treatment. Patients with resected disease who later develop unresectable recurrence without prior systemic therapy remain eligible.
6. ECOG performance status of 0 or 1.
7. Life expectancy ≥6 months per treating physician's assessment.
8. Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of study treatment.
9. Patients must be able to swallow oral tablets.

Exclusion Criteria:

1. Hematology laboratory values of:

   1. Absolute neutrophil count ≤1500 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 (AST) or alanine aminotransferase (ALT):

   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 \>1.7 mg/dL × ULN.
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. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
9. Positive pregnancy test, pregnant, or breastfeeding for all women of child-bearing potential.
10. Per treating physician's assessment, any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.
11. 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 the New York Heart Association as Class III or IV
    6. Unstable angina pectoris.
12. Myocardial infarction within the past 6 months from consent.
13. Active bleeding diathesis.
14. Current complaints of persistent constipation or history of chronic constipation, untreatable bowel obstruction, or fecaloma within the past 6 months from consent.
15. Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other systemic immunosuppressive agents. Topical or nasal corticosteroids are allowed.
16. Known history and/or uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2.
17. History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption.
18. History of malignancy or active treatment for malignancy other than CRC (i.e., radiation or chemotherapy, including monoclonal antibodies) within 5 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.
19. 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 from consent. Note: Influenza vaccine will be allowed if administered \>21 days.
20. Receipt of any investigational agent or study treatment within the past 30 days from consent for a condition other than CRC.
21. Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months from consent for a condition other than CRC.
22. Uncontrolled hypertension
23. Active infection requiring treatment
24. Recent history of major surgery
25. Thromboembolic events during the past 6 months
26. Adults unable to consent
27. Prisoners

Where this trial is running

Houston, Texas

• Houston Methodist Neal Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Maen Abdelrahim, MD, PhD, Pharm D — The Methodist Hospital Research Institute
• Study coordinator: Safiya Joseph

Conditions Metastatic Colorectal Cancer; first line; CRC; metastatic