Randomized Controlled Trial of Induction Chemotherapy with Irinotecan, Folinic Acid, and Oxaliplatin Followed by Chemoradiotherapy for Locally Recurrent Rectal Cancer

The primary objective of this clinical trial is to compare the rate of resections with clear resection margins between both arms in patients with **locally recurrent rectal cancer**. Achieving clear resection margins is clinically significant as it is associated with a reduced risk of cancer recurrence and improved patient outcomes.

Secondary objectives include:

• Comparing local re-recurrence free survival, progression free survival, metastasis free survival, disease free survival, and overall survival between both arms.
• Determining and comparing the pathologic response and objective radiological response to neoadjuvant treatment.
• Assessing and comparing the toxicity and compliance related to induction chemotherapy and chemoradiotherapy between both arms.
• Comparing the number of patients undergoing surgery, surgical characteristics, and the rate of major surgical complications between both arms.
• Comparing the quality of life between both arms.
• Determining the cost-effectiveness and utility of the treatments.
• Systematically collecting blood and tissue samples for future translational research.

The clinical trial involves participants diagnosed with **locally recurrent rectal cancer**. The study population includes both male and female subjects aged 18 years or older. Participants are required to have a confirmed diagnosis of locally recurrent rectal cancer following total or partial mesorectal resection for rectal or distal sigmoidal cancer. The trial includes individuals with resectable disease as determined by magnetic resonance imaging (MRI) or those deemed resectable after neoadjuvant treatment with chemoradiotherapy. Participants must have a World Health Organization (WHO) performance score of 0-1 and provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, controlled, parallel arms study to evaluate the efficacy of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as a neoadjuvant treatment for **locally recurrent rectal cancer**. The trial is open-label, meaning both the researchers and participants are aware of the treatment being administered. The primary objective is to compare the rate of resections with clear resection margins between the two treatment arms. The trial is expected to run from November 2020 to November 2027, with participant recruitment starting in 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), confirmed diagnosis of locally recurrent rectal cancer, and a WHO performance score of 0-1. Following the screening, eligible participants will be randomized into one of the two treatment arms. The trial includes multiple follow-up visits to monitor treatment response and safety, with assessments of primary and secondary endpoints such as local re-recurrence free survival, progression-free survival, and overall survival. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 12 months, depending on the treatment arm and individual response.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The trial will utilize a range of pharmaceutical products, including **irinotecan hydrochloride trihydrate**, **folinic acid**, **tegafur**, **gimeracil**, **oteracil**, **oxaliplatin**, **fluorouracil**, and **capecitabine**, administered via intravenous, oral, or infusion routes as appropriate. The study aims to provide valuable insights into the optimal neoadjuvant treatment strategy for improving surgical outcomes in patients with locally recurrent rectal cancer.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Irinotecan Hydrochloride medac** is provided as a 20 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 180 mg/m² and a total dose not exceeding 1080 mg/m² over a treatment period of up to 12 weeks. The active substance, **irinotecan hydrochloride trihydrate**, is of chemical origin.

**Calcium Folinate** is administered as a 10 mg/ml solution for injection. This medication is also given intravenously, with a maximum daily dose of 400 mg/m² and a total dose limit of 2400 mg/m² over the same treatment duration. The active substance, **folinic acid**, is chemically derived and is also known as leucovorin.

**Teysuno** is provided in the form of hard capsules containing 15 mg of tegafur, 4.35 mg of gimeracil, and 11.8 mg of oteracil. This medication is administered orally, with a maximum daily dose of 50 mg/m² and a total dose not exceeding 2800 mg/m² over 12 weeks. The active substances, **tegafur, gimeracil, and oteracil**, are all of chemical origin.

**Oxaliplatin** is available as a 5 mg/ml concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 130 mg/m² and a total dose limit of 520 mg/m² over the treatment period. The active substance, **oxaliplatin**, is chemically synthesized.

**Fluorouracil** is provided as a 50 mg/ml solution for injection. This medication is administered via infusion, with a maximum daily dose of 2400 mg/m² and a total dose not exceeding 31200 mg/m² over 12 weeks. The active substance, **fluorouracil**, is of chemical origin.

**Xeloda** is administered as 150 mg film-coated tablets. This medication is taken orally, with a maximum daily dose of 2000 mg/m² and a total dose limit of 112000 mg/m² over the treatment period. The active substance, **capecitabine**, is chemically derived.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Each medication is used in accordance with its approved pharmaceutical form and route of administration, ensuring adherence to the trial protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of clear resection margins after surgery, which will be used to evaluate the effectiveness of the treatment in achieving successful surgical outcomes. Secondary endpoints include a range of measures such as local re-recurrence free survival, progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival. These endpoints will provide a comprehensive assessment of the treatment's impact on disease progression and patient survival.

Additional secondary endpoints include pathologic and radiological responses, systemic therapy-related toxicity as per NCI-CTCAE v5.0 grade ≥3, the number of patients completing neoadjuvant treatment, surgical characteristics, and major postoperative complications (Clavien-Dindo ≥3) up to 90 days postoperatively. Quality of life and cost-effectiveness will also be evaluated to assess the broader impact of the treatment on patients' well-being and healthcare resources.

The trial will employ various tools and methods to measure these endpoints, including imaging techniques such as magnetic resonance imaging (MRI) to determine resectability and assess radiological response. The pathologic response will be evaluated through histopathological examination of resected tissues. Patient-reported outcomes and validated scales will be used to assess quality of life. The schedule for measuring and collecting these efficacy parameters will be aligned with the treatment and follow-up phases of the trial, ensuring comprehensive data collection throughout the study duration.