Evaluation of Organ Preservation in Early-Stage Rectal Cancer Using Oxaliplatin, Capecitabine, and Radiotherapy with Additional Local or Systemic Treatment

The primary objective of this study is to assess the rates of successful **organ preservation** in patients with early-stage rectal cancer. This is clinically relevant as it aims to evaluate the potential for non-invasive treatment strategies, which could reduce the need for radical surgery and its associated morbidities, thereby improving patient quality of life.

Secondary objectives include evaluating the **toxicity** of additional treatment options and their impact on both functional and oncological outcomes. This is important for understanding the balance between treatment efficacy and adverse effects, guiding optimal therapeutic strategies for early-stage rectal cancer.

The clinical trial involves participants diagnosed with **early-stage rectal cancer**, specifically defined as early rectal cancer cT1-3abN0M0 or early-intermediate rectal cancer cT1-3abN1 (≤3 nodes ≤8mm)M0. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have a biopsy-proven adenocarcinoma of the rectum, with the tumor located in the distal or mid-rectum necessitating total mesorectal excision (TME) surgery. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants are able and willing to provide written informed consent for the study.

The clinical trial is designed to evaluate the efficacy of organ preservation strategies in patients with **early-stage rectal cancer**. This is a Phase 4, randomized, double-blind, controlled trial, which aims to assess the successful organ preservation rates in the study arms. The trial will involve the administration of **oxaliplatin** via intravenous infusion and **capecitabine** orally, both of which are oncolytic agents used in the treatment of rectal cancer. The trial is expected to commence recruitment on October 1, 2024, and is estimated to conclude by October 1, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as biopsy-proven adenocarcinoma of the rectum, early-stage cancer classification, and an ECOG performance status of 0-1. Following the screening, participants will be randomized into different treatment arms. The trial will include follow-up visits to monitor treatment-related toxicity, clinical response, and any complications. The primary endpoint is the proportion of patients achieving successful organ preservation at 24 months from the start of treatment. Secondary endpoints include treatment-related toxicity, clinical response rates, and overall survival metrics.

The expected length of participant involvement is up to 36 months, with regular assessments to evaluate health-related quality of life and functional outcomes. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data for analysis. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and scientific integrity.

The clinical trial involves the administration of **oxaliplatin**, a chemical compound classified under the ATC code L01XA03, which is a platinum-based oncolytic agent. The pharmaceutical form of oxaliplatin is denoted as PHF00230MIG. It is administered via **intravenous infusion**. The dosing regimen for oxaliplatin is specified as a maximum daily dose of 130 mg/m², with a total maximum dose of 390 mg/m² over a treatment period of up to 9 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.

Additionally, the trial includes the use of **capecitabine**, an antimetabolite and pyrimidine antagonist, classified under the ATC code L01BC06. Capecitabine is provided in the pharmaceutical form PHF00009MIG and is administered **orally**. The dosing for capecitabine is set at a maximum daily dose of 1000 mg/m², with a cumulative maximum dose of 42000 mg/m² over a 9-week treatment period. As with oxaliplatin, compliance with the dosing schedule is closely monitored to maintain the integrity of the trial data.

Both oxaliplatin and capecitabine are utilized as test agents in this study, with no pediatric formulations involved. The trial does not include any orphan drug designations for these substances. The study aims to evaluate the efficacy of these treatments in the context of early-stage rectal cancer, with a focus on organ preservation rates. No additional non-experimental treatments, such as standard-of-care therapy or placebo, are specified in the trial protocol.

Efficacy in the clinical trial titled "STARTREC - Can we Save the rectum by watchful waiting or transanal surgery following short- or long-course radioTherapy and Additional local oR systemic Treatment for early-stage REctal Cancer?" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients with successful organ preservation at 24 months from the start of treatment. This will be measured to determine the effectiveness of the treatment strategies in maintaining organ integrity without the need for radical surgery.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of treatment efficacy and patient outcomes. These include:

• Patient- and clinician-reported acute and late treatment-related toxicity.
• Proportion of patients with a clinical complete response at 26 weeks after treatment onset.
• Proportion of patients undergoing transanal local excision.
• Complications within the first 30 days post-treatment or salvage TME-surgery, assessed by Clavien-Dindo classification.
• Proportion of patients with a stoma at 12 months.
• Time to event of organ loss for patients preferring organ preservation.
• Regrowth rate at 36 months, defined as endoluminal or locoregional nodal regrowth.
• **Metastasis-free survival** to 24 months.
• Non-regrowth-disease free survival to 24 months.
• Overall survival to 36 months.
• Health Related Quality of Life (HR QoL) measured by EORTC questionnaires and Decision Regret Scale.
• Functional outcomes including bowel, bladder, and sexual dysfunction assessed by LARS score and ICIQ questionnaires.

These endpoints will be measured at specified timepoints, including baseline, 6 months, 12 months, 24 months, and 36 months, using validated scales and questionnaires. The analysis will focus on comparing the efficacy of different treatment arms in achieving the desired clinical outcomes while maintaining quality of life for patients with early-stage rectal cancer.