Phase II-III Multicentric Trial on Tailored Management of Locally-Advanced Rectal Carcinoma with Irinotecan Hydrochloride and Drug Combination

The primary objective of this multicentric Phase II-III study is to evaluate a **de-escalation treatment strategy** for patients with locally-advanced rectal carcinoma who are good responders to neoadjuvant chemotherapy (NACT). In Phase II, the focus is on maintaining a satisfactory R0 resection rate of 90%. In Phase III, the study aims to ensure that the de-escalation strategy achieves a 3-year disease-free survival (DFS) rate that is non-inferior to current standards. This is clinically relevant as it seeks to optimize treatment efficacy while potentially reducing treatment-related morbidity.

Secondary objectives include:

• Estimating the compliance rate of the therapeutic schedule.
• Assessing the pathological complete response rate.
• Evaluating overall survival.
• Specifying the efficiency of MRI for prognosis in DFS.
• Evaluating disease-free survival for phase III adaptive design.
• Assessing the metastatic recurrence rate and disease-free survival.
• Evaluating the safety of neoadjuvant chemotherapy and radiochemotherapy.
• Assessing operative morbidity and post-operative morbidity.
• Estimating the sphincter-saving surgery rate.
• Evaluating functional results, including digestive, urinary, and sexual functions.
• Assessing the quality of life using QLQ-C30+CR29.

The clinical trial focuses on patients diagnosed with **rectum cancer**, aiming to evaluate a de-escalation treatment strategy for those who respond well to neoadjuvant chemotherapy. The study population includes both male and female participants, with an age range encompassing adults and older adults. Participants are required to have a general health status that allows for radical pelvic surgery and systemic therapy with Capecitabine. The trial does not include vulnerable populations. The selection criteria emphasize patients with a tumor regression of at least 60% and a circumferential resection margin of at least 1mm, with no clear evidence of metastatic disease on a CT scan. Adequate hematologic, hepatic, renal, and ionogram functions are necessary, assessed within seven days prior to the study treatment. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the tailored management of **locally-advanced rectal carcinoma** following a favorable response to induction chemotherapy. This is a multicentric Phase II-III study with a randomized, double-blind, controlled design. The trial aims to assess a de-escalation treatment strategy for patients who respond well to neoadjuvant chemotherapy (NACT), ensuring a satisfactory R0 resection rate and maintaining the current three-year disease-free survival (DFS) in a non-inferiority trial. The trial is expected to run from November 26, 2021, to November 25, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a tumor regression of at least 60%, no evidence of metastatic disease, and adequate organ function. Following the screening, participants will be randomized and receive treatment with **irinotecan hydrochloride**, **capecitabine**, **oxaliplatin**, **calcium folinate**, and **fluorouracil**. The treatment regimen includes both oral and infusion routes, with specific dosing schedules tailored to each medication. The maximum treatment period varies, with some medications administered for up to 12 cycles.

Follow-up visits will be conducted to monitor the primary endpoints, which include the R0 resection rate and the three-year DFS. Secondary endpoints will assess various outcomes such as compliance with the therapeutic schedule, sphincter-saving surgery rates, and quality of life. The end-of-study visit will evaluate the overall survival and safety of the treatment regimen, using the NCI-CTCAE version 5.0 scale to assess adverse events. Participants are expected to be involved in the study for the duration of the treatment and follow-up periods, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The clinical trial involves the administration of several **chemotherapy** agents, each with specific dosing regimens and administration routes. **Irinotecan Hydrochloride** is provided as a solution for infusion. The maximum daily dose is 180 mg/m², with a total maximum dose of 1080 mg/m² over a treatment period of up to 12 weeks. The infusion route is utilized for administration, and participant compliance is monitored through scheduled dosing and infusion records.

**Capecitabine** is administered in the form of film-coated tablets, taken orally. The maximum daily dose is 1600 mg/m², with a total maximum dose of 40000 mg/m² over a treatment period of up to 5 weeks. Compliance is monitored through pill counts and patient diaries to ensure adherence to the oral dosing schedule.

**Oxaliplatin** is also administered as a solution for infusion. The maximum daily dose is 85 mg/m², with a total maximum dose of 510 mg/m² over a treatment period of up to 12 weeks. Infusion records are maintained to monitor compliance and ensure accurate dosing.

**Calcium Folinate** is provided as a solution for injection, with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over a treatment period of up to 12 weeks. The infusion route is used, and compliance is tracked through infusion logs and patient monitoring.

**Fluorouracil** is administered as a solution for infusion, with a maximum daily dose of 2400 mg/m² and a total maximum dose of 14400 mg/m² over a treatment period of up to 12 weeks. Infusion records are used to ensure compliance and proper administration.

All medications are part of a **chemotherapy** regimen, and their administration is carefully monitored to ensure participant safety and adherence to the study protocol. The trial does not include any placebo or comparator treatments, focusing solely on the experimental chemotherapy agents. Compliance monitoring is a critical component of the study, involving regular assessments and documentation of dosing adherence.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the R0 resection rate, defined as a **Circumferential Resection Margin (CRM)** of at least 1 mm, and the 3-year Disease-Free Survival (DFS) rate. These endpoints are critical for evaluating the success of the de-escalation treatment strategy in patients with locally-advanced rectal carcinoma who have shown a favorable response to induction chemotherapy.

Secondary endpoints will provide additional insights into the treatment's efficacy and include the compliance rate of the therapeutic schedule, sphincter-saving surgery rate, pathological complete response rate, and Dworak Grading. Other important measures include rates of Total Mesorectal Excision (TME) grading, distal margin, and the Neoadjuvant Rectal Score. Long-term outcomes will be assessed through 2-3 year local and metastasis recurrence rates, 3-year local and metastasis recurrence-free survival rates, and overall survival rates at 3 and 5 years. Safety and quality of life will also be evaluated using the NCI-CTCAE version 5.0 scale and EORTC QLQ-C30 + CR29 questionnaires at specified timepoints, including randomization, post-surgery, and 4 and 12 months after surgery.