Modified FOLFOXIRI Plus Target Therapy as a First Line Treatment for Advanced Colorectal Cancer a Prospective Phase Two Study

August 26, 2024 updated by: Mohamed Ahmed Abdelaziz, Al-Azhar University

This prospective Phase II study aims to evaluate the efficacy and safety of a modified FOLFOXIRI regimen in the treatment of metastatic colorectal cancer (MCRC). FOLFOXIRI, though effective, is known for its high toxicity, necessitating close monitoring and dose adjustments. .

The primary endpoint is to assess the impact on the objective response rate and evaluate both acute and delayed toxicity. The secondary endpoints include studying the treatment's effectiveness as conversion therapy, along with disease-free survival (DFS) and overall survival (OS). The tertiary endpoint focuses on evaluating predictive and prognostic factors of significance.

This study seeks to balance the efficacy of FOLFOXIRI with a modified dose to minimize toxicity while maintaining therapeutic benefits, providing a potentially safer and effective option for patients with MCRC.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This prospective Phase II clinical trial aims to assess the efficacy and safety of a modified dose regimen of FOLFOXIRI in the treatment of metastatic colorectal cancer (MCRC). FOLFOXIRI is a chemotherapy regimen known for its high toxicity, necessitating close monitoring, dose reductions, and supportive treatments. While previous studies have demonstrated the clinical efficacy of FOLFOXIRI compared to FOLIRI or FOLFOX, the regimen's toxicity remains a significant concern.

Intervention:

Modified FOLFOXIRI Regimen:

Oxaliplatin: 85 mg/m² IV over 2 hours (Day 1) Irinotecan: 150 mg/m² IV over 90 minutes (Day 1) 5-FU: 2400 mg/m² IV over 48 hours infusion (Day 1)

Targeted Therapy:

KRAS/NRAS/BRAF Wild-Type (Left-Sided Tumor): Anti-EGFR treatment with either Panitumumab (6 mg/kg IV over 60 minutes, Day 1) or Cetuximab (500 mg/m² IV, Day 1).

KRAS/NRAS Mutant or Right-Sided Tumor: Bevacizumab (5 mg/kg IV over 30-90 minutes, Day 1).

Treatment Schedule: Administered biweekly for a maximum of 12 cycles (6 months).

G-CSF Prophylaxis: Administered as primary prophylaxis for patients older than 55 and as secondary prophylaxis for those who develop grade ≥3 neutropenia.

Dose Modifications and Treatment-Related Toxicity:

Toxicity will be evaluated after each cycle using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 (National Cancer Institute, 2017).

Dose Reduction Guidelines: A 25% dose reduction will be implemented for specific grade III/IV acute toxicities including neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, mucositis/stomatitis, hand-foot syndrome, peripheral neuropathy, elevated liver enzymes, severe fatigue, hypertension, proteinuria, and dermatologic toxicity.

Treatment Discontinuation: Patients who experience further grade III/IV acute toxicity after dose reduction will be excluded from the study.

Treatment Duration:

Eligible for Surgery: Patients with a favorable response will receive a maximum of 8 cycles before surgical evaluation.

Ineligible for Surgery: Treatment will continue until the completion of 12 cycles, intolerable toxicity, or a maximum duration of 6 months.

Assessments:

Disease Assessment: Performed every 4 cycles (8 weeks) during the induction phase, followed by every 3 months. Quality of life will be evaluated using the EORTC QLQ C30 and CR 29 questionnaires.

Response Assessment: Based on RECIST v1.1 criteria, categorized as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD).

Statistical Analysis:

Survival Analysis: Kaplan-Meier estimates with one-sided log-rank tests will be used to analyze progression-free survival (PFS). Overall survival (OS) will be calculated from the date of histological diagnosis to the date of last follow-up or death.

Data Analysis: Data will be analyzed using IBM SPSS version 26. Quantitative data will be presented as means, standard deviations, and ranges, or as medians with interquartile ranges, depending on distribution. Qualitative data will be presented as frequencies and percentages. Chi-square tests will compare groups with qualitative data. The confidence interval is set at 95%, with a significance threshold of p < 0.05.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
    • Cairo Governorate
      • Cairo, Cairo Governorate, Egypt, 11311
        • Recruiting
        • Al Hussien University Hospital
        • Contact:
        • Principal Investigator:
          • Mohamed A Abdelaziz
        • Sub-Investigator:
          • Wael H El Sheshtawy
        • Sub-Investigator:
          • Hassan KH Hamdy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Histologically confirmed unrespectable or metastatic colorectal cancer with or without primary tumor in situ.

  • Patients were required to have measurable disease according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) (Eisenhauer EA,2009)
  • ECOG PS 0-1 better to exclude PS II as this protocol is known to be toxic
  • Adequate baseline hematology and clinical chemistry labs
  • Adequate cardiac function

Exclusion Criteria:

  • Double Malignancy
  • DPYD mutant patients
  • Peripheral neuropathy grade 3 or higher patient due to other comorbidities
  • Inflammatory bowel syndrome or any other chronic GIT disease
  • Prior exposure to chemotherapy treatment for colorectal cancer in the metastatic setting
  • Patients who have contraindications for one or more of the study protocol drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: modified FOLFOXIRI plus target therapy

  • Pre-Treatment Medications:

    1. Atropine SC: Administered before irinotecan infusion to prevent side effects.
    2. High-Risk Anti-Emetics Regimen: Used to prevent acute and delayed vomiting.

  • Chemotherapy Regimen: All eligible patients will receive the modified FOLFOXIRI regimen as follows:

    • Oxaliplatin: 85 mg/m² IV over 2 hours (Day 1)
    • Irinotecan: 150 mg/m² IV over 90 minutes (Day 1)
    • 5-FU: 2400 mg/m² IV over 48 hours infusion (Days 1)

  • Targeted Therapy: Administered according to NRAS/KRAS status and the location of the primary tumor:

    • KRAS/NRAS/BRAF Wild-Type (Left-Sided Tumor): Anti-EGFR treatment with either Panitumumab (6 mg/kg over 60 minutes, Day 1) or Cetuximab (500 mg/m², Day 1).
    • KRAS/NRAS Mutant or Right-Sided Tumor: Bevacizumab at a dose of 5 mg/kg IV over 30 to 90 minutes (Day 1).
  • Treatment Schedule: The treatment will be administered biweekly for a maximum of 12 cycles (6 months).
Drug: FOLFOXIRI Protocol
as mentioned in Arm description
Other Names:
  • Bevacizumab
  • Panitumumab
  • Cetuximab
  • modified FOLFOXIRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment-related adverse events
Time Frame: 12 months
evaluate treatment-related acute and delayed toxicity
12 months
Objective Response Rate
Time Frame: 6 months
To assess the impact of the treatment on the objective response rate
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Conversion therapy
Time Frame: 4 months

To assess the treatment's efficacy as a conversion therapy, transforming initially unresectable tumors to resectable ones, response rates will be evaluated every 4 treatment cycles according to RECIST v1.1 (Eisenhauer EA, 2009):

Complete Response (CR): Disappearance of all lesions and pathological lymph nodes.

Partial Response (PR): ≥30% decrease in the sum of the longest diameters (SLD) of target lesions, no new lesions, and no progression in non-target lesions.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Progressive Disease (PD): ≥20% increase in SLD or the appearance of new lesions.

Patients eligible for surgery may receive up to 8 cycles before surgical evaluation. Those showing favorable response will be referred for potential surgical intervention.
4 months
Progression free survival
Time Frame: 12 months
to study the impact of treatment on progression free survival
12 months
Overall survival
Time Frame: 24 months
to study the impact of treatment on overall survival
24 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prognostic and predictive values
Time Frame: 24 month
To evaluate predictive and prognostic factors of significance and its impact ORR, PFS and OS
24 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Al-Azhar University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 17, 2024

Primary Completion (Estimated)

September 1, 2025

Study Completion (Estimated)

September 1, 2026

Study Registration Dates

First Submitted

August 25, 2024

First Submitted That Met QC Criteria

August 26, 2024

First Posted (Actual)

August 28, 2024

Study Record Updates

Last Update Posted (Actual)

August 28, 2024

Last Update Submitted That Met QC Criteria

August 26, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FOXIRI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

study protocol and statistical analysis will be shared

Study Data/Documents

  1. Informed Consent Form

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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