Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676)

Study Overview
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Brief Summary
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This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with BCG, compared to BCG monotherapy, in participants with HR NMIBC that is either persistent or recurrent following adequate BCG induction (Cohort A), or that is naïve to BCG treatment (Cohort B). The primary hypothesis for Cohort A is that the combination of pembrolizumab plus BCG has a superior complete response rate (CRR) as assessed by central pathology review compared to BCG in participants with carcinoma in situ (CIS). The primary hypothesis for Cohort B is that the combination of pembrolizumab plus BCG (either reduced maintenance or full maintenance) has a superior Event Free Survival (EFS) compared to BCG.

Official Title
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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)

Conditions
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High-risk Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: BCG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have locally and blinded independent central review (BICR)-confirmed histological diagnosis of high-risk non-muscle invasive (T1, high grade Ta and/or CIS) UC of the bladder Has undergone cystoscopy/ transurethral resection of bladder tumor (TURBT) to remove all resectable disease Has provided tissue for biomarker analysis Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Has adequate organ function During the treatment period and for ≥7 days after the last dose of BCG, male participants are EITHER abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent, OR, must agree to use contraception unless confirmed to be azoospermic Female participants who are not pregnant, not breastfeeding, and either not a woman of child bearing potential (WOCBP); or are a WOCBP who agrees to use a contraception method that is highly effective or remains abstinent from heterosexual intercourse during the treatment period and for ≥7 days after the last dose of BCG or 120 days after the last dose of pembrolizumab, whichever comes last BCG Post-induction Cohort (Cohort A) Only Has been treated with one adequate course of BCG induction therapy for the treatment of HR NMIBC Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC Exclusion Criteria: Has a history of or concurrent locally advanced (i.e., T2, T3, T4) or metastatic UC Has concurrent extra-vesical (i.e, urethra, ureter, renal pelvis) non-muscle invasive urothelial carcinoma or a history of extra-vesical non-muscle invasive UC Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of start of study treatment Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of start of study treatment Has a known additional malignancy that is progressing or requires active treatment within the past 3 years Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has one or more of the following contraindications to BCG: prior BCG sepsis or systemic infection, total bladder incontinence, or an adverse experience to a previous BCG instillation that resulted in treatment discontinuation and precludes retreating with BCG Has an active infection or diagnosis requiring systemic antimicrobial therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of Hepatitis B or known active Hepatitis C virus infection Has current active tuberculosis Has had an allogenic-tissue/solid organ transplant Has any contraindication(s) to IV contrast or is otherwise unable to have screening imaging with IV contrast performed BCG Post-induction Cohort (Cohort A) Only - Has persistent T1 disease following an induction course of BCG BCG Naïve Cohort (Cohort B) Only - Has received any prior treatment with BCG for their NMIBC within the past 2 years prior to study entry

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1)<br>Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses ( 2 years). | Biological: Pembrolizumab<br>* Pembrolizumab IV infusion of 200 mg Q3W for BCG Post-Induction Cohort (Cohort A), or IV infusion of 400 mg Q6W for BCG Naïve Cohort (Cohort B), according to randomization<br>* Other names: MK-3475;Biological: BCG<br>* BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy<br>* Other names: OncoTICE®;|
| Experimental: BCG Monotherapy: Post-induction Cohort A (Arm A-2)<br>Participants receive BCG monotherapy (Induction and Maintenance). | Biological: BCG<br>* BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy<br>* Other names: OncoTICE®;|
| Experimental: BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1)<br>Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses ( 1 year). | Biological: Pembrolizumab<br>* Pembrolizumab IV infusion of 200 mg Q3W for BCG Post-Induction Cohort (Cohort A), or IV infusion of 400 mg Q6W for BCG Naïve Cohort (Cohort B), according to randomization<br>* Other names: MK-3475;Biological: BCG<br>* BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy<br>* Other names: OncoTICE®;|
| Experimental: BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2)<br>Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses ( 1 year). | Biological: Pembrolizumab<br>* Pembrolizumab IV infusion of 200 mg Q3W for BCG Post-Induction Cohort (Cohort A), or IV infusion of 400 mg Q6W for BCG Naïve Cohort (Cohort B), according to randomization<br>* Other names: MK-3475;Biological: BCG<br>* BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy<br>* Other names: OncoTICE®;|
| Experimental: BCG Monotherapy: BCG Naïve Cohort B (Arm B-3)<br>Participants receive BCG monotherapy (Induction and Maintenance). | Biological: BCG<br>* BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy<br>* Other names: OncoTICE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A) | CRR is defined as the percentage of participants with CIS achieving a complete response (CR). | Up to  3.5 years | 
| Event-Free Survival (EFS) (Cohort B) | EFS is defined as the time from randomization until urothelial carcinoma (UC)-defined event, or death due to any cause. | Up to  5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS (Cohort A) | EFS is defined as the time from randomization until UC-defined event, or death due to any cause. | Up to  5 years | 
| Recurrence-Free Survival (RFS) (Cohorts A and B) | RFS is defined as the time from randomization until the first occurrence of any UC recurrence, progression, or death due to any cause. | Up to  5 years | 
| Overall Survival (OS) (Cohorts A and B) | OS is defined as the time from randomization to death due to any cause. | Up to  5 years | 
| Disease Specific Survival (DSS) (Cohorts A and B) | DSS is defined as the time from randomization to death due to bladder cancer. | Up to  5 years | 
| Time to Cystectomy (Cohorts A and B) | Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy. | Up to  5 years | 
| 12-Month EFS Rate (Cohort A) | EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 12-month EFS rate is defined as the percentage of participants with EFS at 12 months. | 12 months after EFS (up to  5 years) | 
| Duration of Response (DOR) (Cohorts A and B) | DOR is defined as the time from first documented CR until end of response or death due to any cause, whichever occurs first. | Up to  5 years | 
| 12-Month DOR Rate (Cohorts A and B) | The 12-month DOR Rate is defined as the percentage of participants with a CR of at least 12 months duration. | 12 months after CR (up to  4.5 years) | 
| Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B) | An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. | Up to  5 years | 
| Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B) | An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. | Up to  5 years | 
| Change 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 (Items 29 and 30) Combined Score (Cohorts A and B) | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented. | Baseline, time of last PRO assessment (up to  2 years) | 
| Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B) | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented. | Baseline, time of last PRO assessment (up to  2 years) | 
| Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B) | The EORTC-QLQ-NMIBC24 is a 24-item questionnaire developed to supplement the EORTC QLQ-C30 in high-risk NMIBC patients. Each item is scored out of 4 total points (1=Not at All to 4=Very Much). All responses are transformed from 0 to 100, with a high score indicating more symptoms or problems. The change from baseline in EORTC-QLQ-NMIBC24 total score will be presented. | Baseline, time of last PRO assessment (up to  2 years) | 
| Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) (Cohorts A and B) | The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being the worst health you can imagine and 100 being the best health you can imagine. The change from baseline in EQ-5D-5L VAS will be presented. | Baseline, time of last PRO assessment (up to  2 years) | 
| Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Cohorts A and B) | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation. | Time of last PRO assessment (up to  2 years) | 
| TTD in the EQ-5D-5L VAS (Cohorts A and B) | The EQ-5D-5L VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being the worst health you can imagine and 100 being the best health you can imagine. TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule. | Time of last PRO assessment (up to  2 years) | 
| CRR by BICR (Cohort B) | CRR is defined as the percentage of participants with CIS achieving a CR. | Up to  3.5 years | 
| 24-Month EFS Rate (Cohort B) | EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 24-month EFS rate is defined as the percentage of participants with EFS at 24 months. | 24 months after EFS (Up to  5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1), anti-PD-1, anti-PD-L1, BCG, HR NMIBC, Patient Reported Outcome (PRO)