Phase 3 Randomized Trial of Nivolumab, Nivolumab with Ipilimumab, or Chemotherapy in MSI-H/dMMR Metastatic Colorectal Cancer

The primary objective of this Phase 3 randomized clinical trial is to compare the **progression-free survival (PFS)** as assessed by blinded independent central review (BICR) between two treatment arms: nivolumab plus ipilimumab (arm B) versus nivolumab alone (arm A) in participants with **microsatellite instability high (MSI-H)** or **mismatch repair deficient (dMMR) metastatic colorectal cancer**. This comparison is crucial for determining the efficacy of combination immunotherapy versus monotherapy in this patient population, potentially impacting treatment guidelines and patient outcomes.

Secondary objectives include:

• Comparing the overall response rate (ORR) by BICR between arm B and arm A, and overall survival (OS) between these arms.
• Estimating PFS by investigator assessment between arm B and arm A, and PFS by BICR in locally determined dMMR/MSI-H mCRC between these arms.
• Comparing PFS by BICR between arm B and chemotherapy arm (arm C), and ORR by BICR between arm B and chemotherapy.
• Estimating PFS by BICR between arm A and arm C, OS between arm B and arm C, and ORR by BICR between arm A and arm C.
• Estimating PFS by BICR in participants with confirmed dMMR/MSI-H mCRC by each central test in 1L setting between arm B and arm C, and across all lines between arm B and arm A.
• Estimating PFS and ORR by BICR in a crossover cohort.

The clinical trial involves a total of **264 participants** diagnosed with **Microsatellite Instability High (MSI-H)** or **Mismatch Repair Deficient Metastatic Colorectal Cancer (dMMR)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of recurrent or metastatic colorectal cancer, irrespective of prior treatment history, and a known tumor MSI-H or dMMR status. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, indicating a relatively stable general health status. The study also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of **nivolumab** alone, in combination with **ipilimumab**, or compared to investigator's choice chemotherapy in participants with **microsatellite instability high (MSI-H)** or **mismatch repair deficient (dMMR) metastatic colorectal cancer**. The trial aims to assess progression-free survival (PFS) and overall response rate (ORR) as primary and secondary endpoints, respectively, with evaluations conducted by blinded independent central review (BICR). The study is expected to run from September 2019 to June 2026, with participant involvement potentially lasting up to 36 months, depending on the treatment arm and individual response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed recurrent or metastatic colorectal cancer and known tumor MSI-H or dMMR status. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments of PFS and ORR, as well as overall survival (OS) metrics. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.

Participant involvement may be terminated early if criteria such as disease progression, withdrawal of consent, or adverse events necessitate discontinuation. The trial's design ensures that all participants receive treatment via **intravenous use**, with the investigational products being **YERVOY** (ipilimumab), **OPDIVO** (nivolumab), and various chemotherapeutic agents. The study's methodology and procedures are structured to maintain scientific rigor and ensure the collection of reliable data to evaluate the therapeutic potential of the investigational treatments in this patient population.

The clinical trial involves the administration of several experimental and comparator medications. **YERVOY** (ipilimumab) is provided as a 5 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 1 mg/kg. The treatment period can extend up to 999 days. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is labeled specifically for clinical trial use.

**OPDIVO** (nivolumab) is another experimental medication used in this trial. It is available as a 10 mg/mL concentrate for solution for infusion and is administered intravenously. The maximum daily dose is 480 mg, with a treatment period of up to 36 weeks. This product is also manufactured by Bristol-Myers Squibb Pharma EEIG.

**Irinotecan Bendalis** is a comparator treatment in this study. It is a 20 mg/ml concentrate for solution for infusion, administered intravenously. The maximum daily dose is 180 mg/m², with a treatment period of up to 24 weeks. This product is manufactured by Bendalis GmbH and is over-labeled for clinical trial purposes.

**Avastin** (bevacizumab) is used as a comparator treatment. It is provided as a 25 mg/ml concentrate for solution for infusion, administered intravenously. The maximum daily dose is 5 mg/kg, with a treatment period of up to 24 weeks. This product is manufactured by Roche Registration GmbH and is over-labeled for clinical trial use.

**5-FU medac** (fluorouracil) is another comparator treatment. It is available as a 50 mg/ml solution for injection, administered intravenously. The maximum daily dose is 2400 mg/m², with a treatment period of up to 24 weeks. This product is manufactured by Medac Gesellschaft für klinische Spezialpräparate mbH (Wedel) and is labeled for clinical use.

**Oncofolic** (disodium folinate) is also used as a comparator treatment. It is provided as a 50 mg/ml solution for injection/infusion, administered intravenously. The maximum daily dose is 400 mg/m², with a treatment period of up to 24 weeks. This product is manufactured by Medac Gesellschaft für klinische Spezialpräparate mbH (Wedel) and is labeled for clinical use.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to compare the efficacy of nivolumab alone, nivolumab in combination with ipilimumab, and investigator’s choice chemotherapy in participants with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** by Blinded Independent Central Review (BICR) comparing the nivolumab plus ipilimumab arm (arm B) with the nivolumab arm (arm A) across all lines, as well as comparing arm B with the chemotherapy arm (arm C) in the first-line setting. Secondary endpoints encompass a range of measures such as Overall Response Rate (ORR) by BICR, Overall Survival (OS), and PFS by Investigator Assessment, among others. These endpoints will be evaluated across different arms and lines of treatment, with some assessments being centrally confirmed and others based on local testing.

The trial will utilize BICR to ensure unbiased evaluation of PFS and ORR, with assessments conducted at specified intervals throughout the study. The efficacy parameters will be collected and analyzed according to the trial protocol, ensuring consistency and reliability in the data. The trial is designed to provide a comprehensive evaluation of the efficacy of nivolumab alone, nivolumab in combination with ipilimumab, and investigator’s choice chemotherapy in participants with **microsatellite instability high (MSI-H)** or **mismatch repair deficient (dMMR)** metastatic colorectal cancer.