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

Al-Azhar University

Status and phase: Enrolling; Phase 2

Conditions: Neoplasm Malignant; Colon Cancer Stage 4

Treatments: Drug: FOLFOXIRI Protocol

Study type: Interventional

Funder types: Other

Identifiers

NCT06575127

FOXIRI

Details and patient eligibility

About

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.

Full 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.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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60 participants in 1 patient group

modified FOLFOXIRI plus target therapy

Experimental group

Description:

* 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).

Treatment:

Drug: FOLFOXIRI Protocol