Phase III Randomized Trial of Preoperative Chemotherapy vs. Chemotherapy Plus Chemoradiotherapy in Locally Advanced Resectable Rectal Carcinoma

The primary objective of this study is to demonstrate the **non-inferiority** of preoperative chemotherapy alone compared to chemotherapy followed by chemoradiotherapy in terms of oncologic outcomes for patients with locally advanced resectable low or middle rectal cancer, specifically classified as cT3N0 and/or cT1-T3N+. This is clinically relevant as it may offer a less intensive treatment option with potentially fewer side effects while maintaining efficacy in managing rectal carcinoma.

The clinical trial involves participants diagnosed with **middle or low locally advanced resectable rectal carcinoma**. The study population includes both male and female subjects aged 18 years and older, with a **World Health Organization (WHO/ECOG) performance status** of 0 or 1, indicating they are in good general health. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including histologically proven rectal carcinoma located ≤ 12 cm from the anal verge, as determined by MRI, and specific pretreatment imaging workup results. The trial does not include a vulnerable population. Participants are required to use adequate birth control measures if they are of childbearing or reproductive potential. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the non-inferiority of preoperative chemotherapy alone compared to chemotherapy followed by chemoradiotherapy in patients with locally advanced resectable rectal cancer. The trial aims to assess oncologic outcomes, specifically focusing on 3-year progression-free survival as the primary endpoint. The study involves the administration of **irinotecan hydrochloride**, **calcium folinate**, **fluorouracil**, and **oxaliplatin** via **intravenous infusion**. The trial is expected to run from June 2019 to December 2030, with participant involvement lasting up to 10 weeks, depending on the treatment regimen.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven middle or low rectal carcinoma, specific tumor staging, and a World Health Organization performance status of 0 or 1. Following the screening, participants will be randomized into one of the treatment arms. Regular follow-up visits will be scheduled to monitor treatment response and manage any adverse events. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the primary and any secondary endpoints.

Participants are expected to adhere to the study protocol, including the use of adequate birth control measures during the treatment period and for at least six months after the last study treatment. Conditions that may lead to early termination from the study include significant protocol deviations, withdrawal of consent, or adverse events that compromise participant safety. The trial is conducted under strict regulatory compliance to ensure the integrity and reliability of the data collected.

The clinical trial involves the administration of several **experimental medications** for the treatment of locally advanced resectable rectal cancer. **Irinotecan hydrochloride** is administered as an intravenous infusion. The pharmaceutical form is designated as PHF00230MIG. The maximum daily dose is 180 mg/m², with a total maximum dose of 1080 mg/m² over a treatment period of 10 days. This medication is a chemical substance and is not formulated for pediatric use.

**Calcium folinate**, also known as leucovorin calcium, is used in two different pharmaceutical forms: PHF00231MIG and PHF00190MIG. Both forms are administered via intravenous infusion. The PHF00231MIG form has a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m², while the PHF00190MIG form allows for a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg/m². The treatment period for both forms is 10 days. Calcium folinate is a chemical substance and is not intended for pediatric use.

**Fluorouracil**, also known by synonyms such as 5-fluorouracil and 5-FU, is administered as an intravenous infusion in the pharmaceutical form PHF00231MIG. The maximum daily dose is 2400 mg/m², with a total maximum dose of 14400 mg/m² over a 10-day treatment period. This chemical substance is not formulated for pediatric use.

**Oxaliplatin** is administered via intravenous infusion in the pharmaceutical form PHF00230MIG. The maximum daily dose is 85 mg/m², with a total maximum dose of 510 mg/m² over a 10-day treatment period. Oxaliplatin is a chemical substance and is not intended for pediatric use.

All medications are administered as part of a regimen to evaluate the non-inferiority of preoperative chemotherapy compared to chemotherapy followed by chemoradiotherapy in patients with locally advanced resectable rectal cancer. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of 3-year progression-free survival from the time of randomization. This endpoint is designed to evaluate the effectiveness of preoperative chemotherapy alone compared to chemotherapy followed by chemoradiotherapy in patients with locally advanced resectable low or middle rectal cancer. The trial aims to demonstrate the non-inferiority of the chemotherapy-only approach on oncologic outcomes.