Evaluation of Induction Chemotherapy with FOLFOXIRI in High-Risk Locally Advanced Rectal Cancer: A Study on Pathological and Clinical Response Rates

The primary objective of this study is to evaluate whether the addition of induction chemotherapy with **FOLFOXIRI** results in a higher pathological complete response (pCR) rate and clinical complete response (cCR) rate at one year in patients with high-risk locally advanced rectal cancer (hr-LARC). This is compared to existing literature on hr-LARC patients treated with (chemo)radiotherapy alone or followed by consolidation chemotherapy. Achieving a higher pCR and cCR rate is clinically significant as it may indicate improved treatment efficacy and potential for better long-term outcomes in this patient population.

Secondary objectives include:

• Determining recurrence-free survival.
• Assessing distant metastasis-free survival.
• Evaluating progression-free survival.
• Measuring disease-free survival.
• Calculating overall survival.
• Assessing radiological response after induction chemotherapy and after chemoradiotherapy.
• Evaluating pathological response using the Mandard grading system.
• Determining toxicity and compliance related to induction chemotherapy and chemoradiotherapy.
• Assessing the number of patients undergoing surgery and the type and extent of surgery post-neoadjuvant therapy.
• Evaluating major surgical complications rate.
• Assessing quality of life and cost-effectiveness and utility.
• Systematically collecting blood and tissue samples for future translational research.

The clinical trial involves participants diagnosed with **locally advanced rectal cancer**. The study population includes both male and female subjects aged 18 years and older, with a **WHO performance score** of 0-1, indicating they are in good general health and fit for modified dose triple chemotherapy (FOLFOXIRI). The trial does not include a vulnerable population. Participants were selected based on specific imaging criteria confirming high-risk locally advanced rectal cancer, with the disease being resectable or deemed resectable after neo-adjuvant treatment. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified. Key inclusion criteria include histopathologically confirmed rectal cancer with the lower border of the tumor located on or below the sigmoidal take-off as established on MRI of the pelvis. Written informed consent was obtained from all participants. The trial does not focus on any specific lifestyle modifications or restrictions.

The clinical trial is designed to evaluate the efficacy of induction chemotherapy with **FOLFOXIRI** in patients with high-risk locally advanced rectal cancer. This study is a randomized, double-blind, controlled trial, conducted over an estimated duration from June 2021 to June 2025. The primary objective is to assess whether the addition of induction chemotherapy leads to a higher pathological complete response (pCR) and clinical complete response (cCR) rate at one year compared to existing literature on patients treated with (chemo)radiotherapy alone or followed by consolidation chemotherapy. Secondary endpoints include recurrence-free survival, distant metastasis-free survival, progression-free survival, disease-free survival, overall survival, and various other clinical and quality of life measures.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance score, and specific imaging findings. Following the screening, participants will receive treatment with the study drugs, including **irinotecan hydrochloride trihydrate**, **folinic acid**, **fluorouracil**, and **oxaliplatin**, all administered intravenously. The treatment period is set for a maximum of 12 months, with regular follow-up visits to monitor response and any adverse effects. The end-of-study visit will evaluate the overall outcomes and collect final data for analysis.

Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse reactions, non-compliance with the study protocol, or withdrawal of consent. The trial aims to systematically collect data to improve understanding and treatment of high-risk locally advanced rectal cancer, contributing to future translational research.

The clinical trial involves the administration of **Irinotecan Hydrochloride medac**, a concentrate for solution for infusion, with a concentration of 20 mg/ml. The active substance is **irinotecan hydrochloride trihydrate**, and it is administered intravenously. The maximum daily dose is 165 mg/m², with a total maximum dose of 990 mg/m² over a treatment period of up to 12 months. This pharmaceutical form is specifically designed for intravenous infusion, ensuring precise delivery of the medication.

**Calcium Folinate**, also known as **folinic acid**, is provided as a 10 mg/ml solution for injection. This medication is administered intravenously, with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m² over a 12-month period. The solution for injection form allows for rapid administration and absorption of the active substance.

**Fluorouracil Injection** is available as a 50 mg/ml solution for injection. The active substance, **fluorouracil**, is administered intravenously. The maximum daily dose is 3200 mg/m², with a total maximum dose of 38400 mg/m² over a 12-month treatment period. This formulation is intended for direct intravenous injection, facilitating immediate therapeutic action.

**Oxaliplatin** is provided as a 5 mg/ml concentrate for solution for infusion. The active substance, **oxaliplatin**, is administered intravenously. The maximum daily dose is 85 mg/m², with a total maximum dose of 510 mg/m² over a 12-month period. This concentrate is specifically formulated for infusion, ensuring controlled and sustained delivery of the medication.

All medications in this trial are administered intravenously, and participant compliance is monitored through regular assessments and dosing schedules. The trial aims to evaluate the efficacy of these treatments in achieving higher pathological and clinical complete response rates in patients with high-risk locally advanced rectal cancer.

Efficacy in this clinical trial will be assessed primarily by evaluating the pathological complete response (**pCR**) rate and clinical complete response (**cCR**) rate at 1 year in patients with high-risk locally advanced rectal cancer (hr-LARC). These primary endpoints will be compared to existing literature on hr-LARC patients treated with (chemo)radiotherapy alone or followed by consolidation chemotherapy. Secondary endpoints include recurrence-free survival, distant metastasis-free survival, progression-free survival, disease-free survival, and overall survival. Additionally, the trial will assess radiological responses after induction chemotherapy and chemoradiotherapy, pathological response using the Mandard grading system, and toxicity and compliance related to the administration of induction chemotherapy and chemoradiotherapy. Other secondary endpoints involve determining the number of patients undergoing surgery, the type and extent of surgery after neoadjuvant therapy, major surgical complications rate, quality of life, cost-effectiveness and utility, and the systematic collection of blood and tissue samples for future translational research.