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 The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.
Male or female ≥18 years of age.
Histopathological or cytologically confirmed metastatic CRC.
Failed second-line therapy for metastatic disease.
A minimum of one measurable disease per RECISTv1.1.
Absolute neutrophil count ≤1000 cells/mm3
Platelets ≤70,000 cells/mm3
Hemoglobin ≤9 g/dL
>5 × upper limits of normal (ULN) if the documented history of hepatic metastases; or
Parallel
Regorafenib (BAY 73-4506)
DrugRegorafenib 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for 3 weeks on / 1 week off continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.
5FU/LV
Drug5FU/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)
Bevacizumab
DrugBevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15.
Trifluridine-tipiracil
DrugFTD-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.
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.
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.
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.
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).
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).
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).
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