A Phase 3, Randomized, Comparator-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in combination with Bacillus Calmette-Guerin (BCG) in Participants with High-risk Non-muscle Invasive Bladder Cancer (HR NMIBC) that is either Persistent or Recurrent Following BCG Induction or that is Naïve to BCG Treatment (KEYNOTE-676)

The primary objective of this Phase 3 clinical trial is to evaluate the **complete response rate (CRR)** and **event-free survival (EFS)** in participants with high-risk non-muscle invasive bladder cancer (HR NMIBC). Specifically, the study aims to compare the CRR for the combination of pembrolizumab and Bacillus Calmette-Guérin (BCG) versus BCG alone in participants with carcinoma in situ (CIS) in Cohort A. In Cohort B, the trial seeks to compare the EFS between participants receiving pembrolizumab with reduced or full maintenance BCG versus BCG alone. These objectives are clinically relevant as they address the efficacy of pembrolizumab in combination with BCG, potentially offering improved therapeutic options for patients with HR NMIBC.

The secondary objectives include:

• Cohort A: Comparing event-free survival (EFS), recurrence-free survival (RFS), overall survival (OS), disease-specific survival (DSS), and time to cystectomy between treatment groups. Assessing 12-month EFS rate, duration of response (DOR) in CIS participants with a complete response (CR), and 12-month DOR rate in CIS participants with a CR. Determining the safety and tolerability of pembrolizumab + BCG. Evaluating changes in health-related quality of life (HRQoL) scores using EORTC QLQ-C30, EuroQoL EQ-5D-5L, and EORTC QLQ-NMIBC24.
• Cohort B: Comparing CRR for pembrolizumab + BCG (reduced and full maintenance) versus BCG alone in CIS participants. Comparing RFS, OS, DSS, and time to cystectomy between treatment groups. Assessing DOR and 12-month DOR rate in CIS participants. Evaluating the 24-month EFS rate. Determining the safety and tolerability of pembrolizumab + BCG. Evaluating changes in HRQoL scores using the same instruments as in Cohort A.

The clinical trial involves a total of **838 participants** diagnosed with **high-risk non-muscle invasive bladder cancer**. The study population includes both male and female subjects, with age categories ranging from adults to the elderly. Participants were selected based on specific criteria, including a confirmed histological diagnosis of high-risk non-muscle invasive urothelial carcinoma of the bladder, and having undergone cystoscopy or transurethral resection of bladder tumor to remove all resectable disease. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating a range from fully active to capable of self-care but unable to carry out any work activities. Participants are required to have adequate organ function and adhere to specific lifestyle considerations regarding contraception and abstinence during the treatment period. The trial population also includes a vulnerable population, ensuring comprehensive representation. The selection process ensures that participants meet the necessary health and lifestyle criteria to participate in the study effectively.

The clinical trial is designed as a **randomized**, comparator-controlled study to evaluate the efficacy and safety of **pembrolizumab** in combination with **Bacillus Calmette-Guérin (BCG)** in participants with high-risk non-muscle invasive bladder cancer (HR NMIBC). The trial is structured to include two cohorts: Cohort A, which focuses on participants with carcinoma in situ (CIS), and Cohort B, which includes participants receiving reduced or full maintenance therapy. The primary endpoints are the complete response rate (CRR) for Cohort A and event-free survival (EFS) for Cohort B. Secondary endpoints include recurrence-free survival, overall survival, and disease-specific survival, among others.

The trial is expected to span approximately ten years, with an estimated recruitment start date of November 13, 2018, and an anticipated end date of December 31, 2028. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological diagnosis, prior treatment history, and organ function. Following the screening, participants will be randomized to receive either the combination therapy or BCG alone. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any residual effects of the treatment.

Participant involvement is expected to last up to 147 weeks, depending on the cohort and treatment regimen. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression that necessitates alternative treatment. The trial employs a double-blind methodology to ensure unbiased results, with both participants and investigators unaware of the treatment assignments. This design aims to provide robust data on the comparative effectiveness of pembrolizumab and BCG in managing HR NMIBC.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via the **intravenous** route. The maximum daily dose is 400 mg, with a total maximum dose of 7000 mg over a treatment period of up to 105 days. Pembrolizumab is a biological product, specifically a protein of other origin, and is not formulated for pediatric use. The medication is produced by Merck Sharp & Dohme BV and is identified by the sponsor product code MK-3475.

In addition to pembrolizumab, the trial also utilizes **Bacillus Calmette-Guérin (BCG), TICE**, which is a **powder for intravesical suspension**. This non-experimental treatment is administered through **intravesical use**. The maximum daily dose for BCG is 50 mg, with a total maximum dose of 1350 mg over a treatment period of up to 147 days. BCG is classified as a structurally diverse substance, specifically a vaccine, and is also a biological product. It is not intended for pediatric use. The BCG used in this trial does not have a marketing authorization number and is identified by the scientific product code SUB25779.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Complete Response Rate (CRR)** by Blinded Independent Central Review (BICR) for Cohort A and **Event-Free Survival (EFS)** for Cohort B. Secondary endpoints encompass a range of measures such as EFS for Cohort A, Recurrence-Free Survival (RFS), Overall Survival (OS), Disease Specific Survival (DSS), and Time to Cystectomy for both cohorts. Additionally, the trial will evaluate the 12-Month EFS Rate for Cohort A, Duration of Response (DOR), and 12-Month DOR Rate for both cohorts.

Patient-reported outcomes will be assessed through changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life, Physical Functioning, and the Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score. The European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) will also be used. Time to Deterioration (TTD) in these quality of life measures will be monitored. The percentage of participants experiencing adverse events and those discontinuing the study drug due to adverse events will be recorded. The trial will also measure the 24-Month EFS Rate for Cohort B.