This Phase II clinical trial at Houston Methodist Neal Cancer Center is evaluating the safety and efficacy of combining 5-Fluorouracil (5FU) -based chemotherapy (either FOLFIRI: folinic acid, 5FU, irinotecan; or mFOLFOX6: folinic acid, 5FU, oxaliplatin) with fruquintinib as a first-line treatment for patients with locally advanced unresectable or metastatic colorectal cancer. Fifty patients will receive treatment in 28-day cycles, with fruquintinib initially dosed at 4 mg daily and potentially increased to 5 mg if no significant toxicities are observed. After six months, patients showing stable disease or better will transition to a maintenance phase with 5FU and fruquintinib, continuing until disease progression or other discontinuation criteria are met. The primary endpoint is time to progression based on RECIST v1.1 criteria, while secondary endpoints include safety, tolerability, and duration of response. The trial is being conducted across multiple Houston Methodist hospitals and is currently the only first-line CRC trial available in the system. If successful, it could offer a new therapeutic option and inform future treatment guidelines for advanced colorectal cancer.

This is a phase II trial investigating the efficacy and safety of 5-Fluorouracil (5FU)-based therapy in combination with fruquintinib for patients with locally advanced unresectable or metastatic colorectal cancer in the first-line setting at Houston Methodist Neal Cancer Center. Patients will be administered 5FU-based therapy combined with fruquintinib. This study will consist of the 5FU-based therapy administered to 50 patients as FOLFIRI (Irinotecan: 180mg/ m² I.V. 30-90min day 1, LV: 400mg/ m² I.V. 2 hours day 1, 5FU: 400mg/ m² I.V. bolus day 1; 2400mg/ m² I.V. 46-48 hours, in 2 weeks cycle), or mFOLFOX6 (Oxaliplatin: 85mg/ m² I.V. 2 hours day 1, LV: 400mg/ m² I.V. 2hours day1, 5FU: 400mg/ m² I.V. bolus day 1; 2400mg/m 2 I.V. 46-48 hours, in 2 weeks cycle), and fruquintinib orally once daily on days 1-21.The first 3 patients will receive fruquintinib at 4 mg orally once daily of each cycle. If no dose-limiting toxicity (DLT)-like adverse events related to fruquintinib are observed during the first two cycles, then subsequent patients will be enrolled at 5 mg orally once daily. Both fruquintinib and 5FU-based therapy doses will be adjusted as needed according to the Principal Investigator's opinion. Treatments will be 28-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. After six months on the trial treatment, patients who have stable disease, partial response or complete response will transition to maintenance therapy which consists of 5-FU and fruquintinib, continuing until disease progression, unacceptable toxicity, or consent withdrawal. Following the study treatment period, patients who maintain a favorable response will be offered to continue the trial regimen off-protocol. The total study duration is approximately 12 months which encompasses both the initial treatment phase (6 cycles/6months) and the maintenance phase. There is no pre-specified maximum duration for the maintenance phase; treatment will continue until disease progression, unacceptable toxicity, or patient withdrawal. This ensures that patients deriving clinical benefit from the therapy can continue treatment as long as it remains safe and effective.

The primary endpoint will be evaluating the time to progression (TTP) of the patient population according to RECIST v1.1 criteria. A secondary endpoint will be assessing the safety and tolerability of 5FU-based therapy in combination with fruquintinib, as measured through the incidence and severity of treatment-emergent AEs (NCI CTCAE (v5.0)) and change from baseline in the clinical laboratory and physical examination findings. All grades of adverse event rates will be assessed and reported. An additional secondary endpoint will be measuring the duration of response of 5FU-based treatment in combination with fruquintinib in a first-line setting for locally advanced unresectable or metastatic colorectal cancer patients according to RECIST v1.1 criteria and using the investigator's tumor assessment. This study will be conducted within the Houston Methodist System including the Neal Cancer Center with full access to the naïve treatment population at other Houston Methodist community hospitals such as Houston Methodist Baytown Hospital, Houston Methodist Sugar Land Hospital, Houston Methodist Willowbrook Hospital, Houston Methodist West Hospital, Houston Methodist Clear Lake Hospital, Houston Methodist Cypress Hospital, and other Houston Methodist locations. Outreach materials such as brochures, fact sheets, flyers, and posters with our trial information will be compiled and distributed to our Houston Methodist Neal Cancer Center and Health System colleagues. Automated follow-up emails or text messages will remind patients to take the next step with their providers.

This study has no competing trial active at the Houston Methodist System, including the Neal Cancer Center or other community hospitals, making this the only first-line CRC trial available. If successful, the proposed therapy will represent a new option, in the first-line setting, for the treatment of locally advanced unresectable or metastatic colorectal cancer. This single-arm study may provide insights that could inform future guidelines enabling studies to better treat and control CRC.

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

The Clinical Study Report will include analysis of de-identified data and will be shared with the supporter and published when available.