Phase I Trial of 5-Fluorouracil (5FU) -Based Therapy in Combination With Hydroxytyrosol (HT) in Patients With Advanced or Metastatic Colorectal Cancer

This is a phase I study investigating the safety and antitumor activity of 5FU-based therapy (FOLFIRI/FOLFOX + Biologics) in combination with Hydroxytyrosol (HT) as a treatment for patients with advanced or metastatic colorectal cancer. Patients will receive: 1 capsule of HT 25 mg daily for 2 weeks before beginning 5FU-based therapy (FOLFIRI/FOLFOX + Biologics), 1 capsule of HT (25 mg) daily for 2 weeks while receiving the FOLFIRI/FOLFOX + Biologics, until sign of disease progression. The prescribed FOLFIRI/FOLFOX administer as: Irinotecan 180 mg/m² intravenously (IV) over 90 minutes concurrently with Leucovorin 400 mg/m² IV over 120 minutes, followed by Fluorouracil 400-500 mg/m² IV bolus then 2400-3000 mg/m² IV infusion over 4-6 hours with or without, the designated Biologics, a standard dose of Cetuximab or Bevacizumab will be administered in 2-week cycles until disease progression or un-tolerated toxicity

Inclusion Criteria: A subject will be eligible for inclusion in this study only if all the following criteria are met: 1. Male or female ≥18 years of age. 2. Histopathologically or cytologically confirmed advanced or metastatic CRC. 3. Patient who is eligible for first-line therapy for advanced or metastatic CRC, such as 5FU-based therapy. 4. Measurable disease per the RECIST v1.1. 5. Eastern Cooperative Oncology Group performance status of 0 or 1. 6. Life expectancy ≥6 months. 7. Females of childbearing potential must agree to use birth control during the study and for 30 days after your last dose of HT, at least 9 months after your last dose of oxaliplatin, at least 3 months after your last dose of 5-FU, and at least 6 months after your last dose of irinotecan. 8. Male who are sexually active and their partner can become pregnant, must agree to use birth control during the study and for 30 days after their last dose of HT, at least 6 months after their last dose of oxaliplatin, at least 3 months after his last dose of 5-FU, and at least 3 months after his last dose of irinotecan. \- Exclusion Criteria: Subjects must meet all the inclusion criteria listed above in Section 10.1 and none of the following exclusion criteria: 1. Hematology laboratory values of: 1. WBC of \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 \1.5 × ULN or \>1.5 mg/dL. 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. Estimated glomerular filtration rate \21 days. 17. Receipt of any investigational agent or study treatment within the past 30 days. 18. Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months. 19. Patients must be able to swallow oral capsules. 20. Participants with metastatic CRC and microsatellite instability-high or deficient mismatch repair tumors. 21. surgical Surgery, within 12-months or less. 22. For patients to be treated with bevacizumab: history of gastrointestinal fistula or perforation, major surgery within 28 days of study treatment initiation, recent hemorrhage, arterial thromboembolic events or deep venous thrombosis within 6 months, uncontrolled hypertension (i.e., BP \> 150/90 mm Hg), proteinuria, and hemoptysis. \-