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

Summary

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.

Detailed description

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.

Arms & interventions

• DrugFruquintinib Combined With Chemotherapy

  The intervention in this trial involves administering a combination of 5FU-based chemotherapy and fruquintinib to patients with locally advanced unresectable or metastatic colorectal cancer. Patients receive either the FOLFIRI or mFOLFOX6 regimen, both of which include 5-fluorouracil (5FU), leucovorin (LV), and either irinotecan (FOLFIRI) or oxaliplatin (mFOLFOX6). Fruquintinib is given orally once daily for 21 days in each 28-day cycle. The initial dose of fruquintinib is 4 mg daily for the first three patients to assess safety; if no dose-limiting toxicities are observed, the dose is increased to 5 mg daily for subsequent participants. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. After six months, patients with stable disease or better transition to a maintenance phase with 5FU and fruquintinib alone.

Outcome measures

Eligibility criteria