Phase 3 Randomized Study of Perioperative Dostarlimab vs. Standard of Care in Untreated T4N0 or Stage III dMMR/MSI-H Resectable Colon Cancer

The primary objective of this study is to evaluate the **efficacy** of peri-operative dostarlimab compared with standard of care (SOC) in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer. This is clinically relevant as it aims to determine whether dostarlimab can provide a more effective treatment option for this specific patient population, potentially improving outcomes and offering an alternative to existing therapies.

Secondary objectives include:

• Evaluating the efficacy of neo-adjuvant dostarlimab in participants.
• Estimating the difference in overall survival for participants treated with perioperative dostarlimab compared with SOC.
• Evaluating the efficacy of peri-operative dostarlimab compared with SOC.
• Assessing the safety and tolerability of dostarlimab compared with SOC.
• Describing the pharmacokinetics (PK) of dostarlimab in participants.
• Determining the immunogenicity of dostarlimab in participants.

These secondary objectives are crucial for understanding the broader impact of dostarlimab, including its safety profile, potential side effects, and how it is processed by the body, which are essential for its potential integration into clinical practice.

The clinical trial involves a total of **403 participants** diagnosed with untreated T4N0 or Stage III dMMR/MSI-H resectable colon cancer. The study population includes both **male and female** subjects, aged 18 years and older, who are in good general health as indicated by an ECOG performance status of 0 or 1. Participants were selected based on their diagnosis of colon adenocarcinoma, which is resectable and demonstrates either a dMMR status or MSI-H phenotype. The trial includes individuals with known Lynch syndrome who carry specific germline mutations in MMR or EPCAM genes. Participants are required to have adequate organ function and provide a tumor tissue sample obtained at the time of or after the initial diagnosis. The trial population is diverse, including vulnerable populations, and all participants have provided informed consent and agreed to use adequate contraception. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase 3**, open-label, randomized study to evaluate the efficacy of perioperative **dostarlimab** monotherapy compared to the standard of care in participants with untreated T4N0 or Stage III dMMR/MSI-H resectable colon cancer. The trial will involve a comparison between the investigational product, dostarlimab, and standard chemotherapy regimens, including **capecitabine**, **folinic acid**, **oxaliplatin**, and **fluorouracil**. The study is expected to run until December 25, 2030, with recruitment starting on September 1, 2023.

Participants will be randomly assigned to receive either dostarlimab or the standard chemotherapy regimen. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes. The primary endpoint is event-free survival (EFS), with events defined as disease recurrence, progression precluding surgery, recurrence based on pathological assessment, death from any cause, or treatment-related toxicity. Secondary endpoints include pathological response, overall survival (OS), and the frequency and severity of adverse events (AEs).

Participant involvement is expected to last up to 12 months, depending on the treatment arm. Conditions that may lead to early termination from the study include significant treatment-related toxicity, disease progression that precludes surgery, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all data collected is reliable and valid for assessing the efficacy and safety of dostarlimab in this patient population.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Dostarlimab**, marketed as JEMPERLI 500 mg concentrate for solution for infusion, is the primary experimental medication. It is administered intravenously with a maximum daily dose of 500 mg and a total dose of 1000 mg over a treatment period of up to 12 months. Dostarlimab is a protein-based therapeutic agent, and its administration involves the use of a closed system transfer device for the solution in a clinical setting.

**Capecitabine**, available as Xeloda 150 mg and 500 mg film-coated tablets, is used as a comparator treatment. It is administered orally with a maximum daily dose of 2000 mg/m² and a total dose of 1000 mg/m² over a 6-month period. Capecitabine is a chemical substance and is part of the standard-of-care therapy in this trial.

**Folinic Acid**, marketed as Leucovorin-Teva 10 mg/ml concentrate for solution for infusion, serves as a detoxifying agent for antineoplastic treatment. It is administered intravenously with a maximum daily and total dose of 400 mg/m² over a 6-month period. Folinic acid is a chemical substance and is used to mitigate the toxic effects of chemotherapy.

**Oxaliplatin**, available as a 5 mg/ml concentrate for solution for infusion, is another comparator treatment. It is administered intravenously with a maximum daily and total dose of 130 mg/m² over a 6-month period. Oxaliplatin is a chemical substance and is part of the chemotherapy regimen in this study.

**Fluorouracil**, marketed as a 25 mg/ml solution for injection or infusion, is also used as a comparator treatment. It is administered intravenously with a maximum daily and total dose of 1200 mg/m² over a 6-month period. Fluorouracil is a chemical substance and is included in the standard chemotherapy protocol.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of peri-operative dostarlimab compared with standard-of-care treatments in participants with untreated T4N0 or Stage III dMMR/MSI-H resectable colon cancer.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event Free Survival (EFS)**, which will be evaluated through recurrence assessments conducted by Blinded Independent Central Review (BICR). An event is defined as disease recurrence based on radiological assessment by BICR, disease progression precluding surgery (local assessment), disease recurrence based on a pathological assessment of new lesions identified after surgery (local assessment), death due to any cause, or treatment-related toxicity that results in the participant not being suitable for surgery.

Secondary endpoints include pathological response determined by local assessment, overall survival (OS) defined as the time from randomization to death from any cause, and EFS with recurrence assessed by local assessment, where component events are the same as the primary endpoint. Additionally, the frequency and severity of treatment-emergent adverse events (AEs), serious adverse events (SAEs), immune-related adverse events (irAEs), and AEs leading to death or discontinuation of study intervention will be monitored. Serum concentrations and relevant pharmacokinetic (PK) parameters for dostarlimab, such as C-EoI and Ctrough, will be measured, along with the incidence of anti-drug antibodies (ADA) against dostarlimab.