Trial of 5-Fluorouracil (5FU)-Based Therapy in Combination With Fruquintinib in Patients With Locally Advanced Unresectable or Metastatic 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.