Neoadjuvant Dostarlimab and Short-Course Radiotherapy in Microsatellite Unstable or Mismatch Repair-Deficient Locally Advanced Rectal Cancer

The primary objective of this study is to evaluate the **treatment strategy failure** (TSF) rate at 24 months in patients with locally advanced rectal cancer characterized by microsatellite instability or mismatch repair deficiency. TSF is defined as the rate of patients who do not achieve a clinical complete response (cCR) and those who achieve a cCR but experience local or metastatic recurrence or local regrowth within two years. This objective is clinically relevant as it aims to assess the effectiveness of the neoadjuvant treatment strategy involving dostarlimab and short-course radiotherapy in a watch-and-wait approach, potentially impacting treatment protocols for this patient population.

Secondary objectives include:

• Assessment of **tolerability** using NCI-CTCAE v4.0 for treatment and non-treatment related adverse events.
• Evaluation of the rate of **organ preservation** at 2 years.
• Determination of the rate of local excision, TME (total mesorectal excision) surgery, or creation of a permanent colostomy/ileostomy at 2 years.
• Analysis of the quality (R0, completeness of the mesorectum) and morbidity (according to Clavien Dindo and Quirke classification) of local excision or TME or permanent colostomy/ileostomy if needed.
• Measurement of **disease-free survival** (DFS) at 6, 12, 24, and 36 months.
• Assessment of **overall survival** (OS) at 6, 12, 24, and 36 months.
• Evaluation of quality of life score changes using EORTC QLQ-C30 and QLQ-CR29 scales at baseline, 3, 6, 12, and 24 months.
• Assessment of Low Anterior Resection Syndrome score (LARS) at baseline, 3, 6, 12, and 24 months.
• Evaluation of incontinence score (WEXNER) at baseline, 3, 6, 12, and 24 months.
• Assessment of sexual function scales (IIEF5/FDFI) at baseline, 3, 6, 12, and 24 months.

The clinical trial involves participants diagnosed with **rectal cancer** that is locally advanced and characterized by microsatellite instability or mismatch repair deficiency. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of rectal adenocarcinoma with mismatch-repair deficiency or microsatellite instability-high status, determined through immunohistochemistry, PCR, or next-generation sequencing. The trial includes individuals with stage II or III rectal adenocarcinoma located in the middle and lower third of the rectum, as diagnosed by standard clinical and MRI criteria. Participants must have a WHO performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate liver, hematological, and renal function are necessary, with specific laboratory criteria outlined for inclusion. Women of childbearing potential and men who have sex with such women must agree to use contraception during and after the trial. Participants must be able to understand and sign the informed consent form and be affiliated with a social security scheme. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized**, phase II study to evaluate the efficacy of **dostarlimab** in combination with short-course radiotherapy for patients with locally advanced rectal cancer characterized by microsatellite instability or mismatch repair deficiency. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to either the treatment or control group. The primary objective is to assess the treatment strategy failure (TSF) rate at 24 months, defined as the rate of patients without a clinical complete response (cCR) and those with a cCR but experiencing local or metastatic recurrence or regrowth within two years.

The trial is expected to commence recruitment on May 13, 2024, and conclude by December 31, 2029. Participants will be involved in the study for a maximum treatment period of six months, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, histological confirmation of rectal adenocarcinoma, and adequate organ function; regular follow-up visits to monitor treatment response and adverse events; and an end-of-study visit to evaluate the final outcomes and collect data on overall survival, disease-free survival, and quality of life.

Inclusion criteria require participants to be 18 years or older, with histologically confirmed rectal adenocarcinoma and a WHO performance status of 0 or 1. Adequate liver, hematological, and renal function are also necessary. Women of childbearing potential and men with partners of childbearing potential must agree to use contraception during and after the trial. The trial will exclude individuals who do not meet these criteria or who experience significant adverse events during the study. The study aims to provide valuable insights into the potential benefits of dostarlimab in this patient population, with secondary endpoints including adverse events, disease-free survival, overall survival, organ preservation rates, and quality of life assessments.

The clinical trial involves the administration of **JEMPERLI**, a **500 mg concentrate for solution for infusion**. The active substance in JEMPERLI is **dostarlimab**, a protein-based therapeutic agent. The pharmaceutical form of the medication is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 500 mg, with a total maximum dose of 4500 mg over the course of the treatment. The treatment period is limited to a maximum of 6 months. The medication is manufactured by GlaxoSmithKline (Ireland) Limited and is not formulated for pediatric use. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In this study, JEMPERLI is used as an experimental treatment in a randomized phase II trial for patients with microsatellite unstable or mismatch repair-deficient locally advanced rectal cancer. The trial aims to evaluate the treatment strategy failure rate at 24 months. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus is on the efficacy and safety of dostarlimab in the specified patient population.

Efficacy in the clinical trial will be assessed primarily through the evaluation of the **treatment strategy failure (TSF) rate** at 24 months. TSF is defined as the rate of patients who do not achieve a clinical complete response (cCR) and those who achieve a cCR but experience local or metastatic recurrence or local regrowth within two years from the date of randomization. This primary endpoint will provide a measure of the treatment's effectiveness in preventing disease progression or recurrence.

Secondary endpoints include the assessment of **adverse events (AEs)**, which will be evaluated according to the NCI-CTCAE v4.0 criteria. The number of patients experiencing at least one AE will be categorized by maximum grade and causality to the treatment with dostarlimab. **Disease-Free Survival (DFS)** will be measured as the time from randomization to disease recurrence, second colorectal cancer, or death, with assessments at 6, 12, 24, and 36 months. **Overall Survival (OS)** will be determined by the time from randomization to death, with similar timepoint assessments. The rate of **organ preservation** at two years will be calculated based on the absence of primary tumor resection. **Quality of life** will be evaluated using the EORTC QLQ-C30 and QLQ-CR29 scales at baseline, 3, 6, 12, and 24 months, with a focus on the time to final deterioration of the global health score.