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


Eligibility Criteria:
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.

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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 \<3000 and absolute neutrophil count ≤1500 cells/mm3 with the Fy null phenotype.
   2. Platelets ≤100,000 cells/mm3
   3. Hemoglobin ≤9 g/dL (Fe infusion is allowed to correct anemia in iron deficient anemia patients, per standard-of-care)
2. Hepatic laboratory values of aspartate transaminase or alanine aminotransferase:

   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 \>1.5 × 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 \<50 mL/min.
7. Positive pregnancy test, pregnant, or breastfeeding (female patients only).
8. Any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.
9. 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 classified by the New York Heart Association as Class III or IV
   6. Unstable angina pectoris.
10. Myocardial infarction within the past 6 months.
11. Active bleeding diathesis (platelets less than 100,000 or active bleeding)
12. Current complaints of persistent constipation or history of chronic constipation, bowel obstruction, or fecaloma within the past 6 months.
13. Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other immunosuppressive agents
14. Known history and/or uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2.
15. History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption.
16. 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. Note: Influenza vaccine will be allowed if administered \>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.

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