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

Study Overview

• Status: Recruiting
• Conditions: Advanced or Metastatic CRC
• Intervention / Treatment: Drug: Hydroxytyrosol

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jennifer Garrett M Clinical Trials Manager, MSN; Phone Number: 281-222-9983; Email: jmgarrett@houstonmethodist.org
• Study Contact Backup: Name: Kimberly Vu Clinical Research Nurse, BSN; Phone Number: 936-270-2037; Email: kvu2@houstonmethodist.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist.
      • Contact: Jennifer Garrett M Clinical Trials Manager, MSN; Phone Number: 281-222-9983; Email: jmgarrett@houstonmethodist.org
      • Contact: Email: aesmail@houstonmethodist.org
      • Principal Investigator: Maen Abdelrahim, MD, PhD. Pharm D
      • Sub-Investigator: Abdullah Esmail, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hydroxytyrosol (HT) in combination with Folfiri/Folfox; 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

Drug: Hydroxytyrosol; 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; Other Names: Folfiri/Folfox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety, Toxicity, and Pharmacokinetic/Pharmacodynamic (PK/PD) Profile of HT in Combination with FOLFIRI/FOLFOX + Biologics	Evaluation of safety profile, toxicity, and PK/PD parameters in patients receiving HT with 5FU-based therapy according to NCI CTCAE v5.0.	Through study completion, up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) at 6 and 12 Months	Measurement of PFS at 6 months and 12 months, based on tumor assessment using RECIST v1.1 criteria.	6 and 12 months post study drug initiation
Objective Response Rate (ORR) According to RECIST v1.1	Proportion of patients achieving partial response (PR) or complete response (CR) as per RECIST v1.1.	Through study completion, up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Health-Related Quality of Life (QoL)	Assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).	Baseline, 6 months, and 12 months
Immune T-Cell Profiling in Blood and Tissue Samples	Analysis of T-cell clusters in pretreatment tissue and blood and on-treatment blood (after 2 weeks on HT alone). Evaluation of CD4+, CD8+ T cells, and CD8+ T-cell:Treg ratio using multiplexed IF & single-cell RNA sequencing (scRNA-seq).	Baseline, 2 weeks after HT initiation, and up to 100 weeks (from baseline to disease progression)
Assessment of Tissue Immune Cells	Quantification of tissue immune cells using flow cytometry.	Baseline and post-treatment biopsy (up to 100 weeks, at disease progression or prior to surgery, if applicable)
Analysis of Regulatory Proteins and Plasma Cytokines	Evaluation of regulatory proteins and plasma cytokines using a multiplexed protein array.	Baseline and post-treatment biopsy (up to 100 weeks, at disease progression or prior to surgery, if applicable)

Collaborators and Investigators

• Sponsor: The Methodist Hospital Research Institute
• Investigators: Study Director: Abdullah Esmail, MD, Houston Methodist Neal Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 15, 2025
• First Submitted That Met QC Criteria: February 13, 2025
• First Posted (Actual): February 19, 2025

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Anti-Infective Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Antioxidants; Protective Agents; 3,4-dihydroxyphenylethanol; Folfox protocol
• Other Study ID Numbers: Pro00038031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No