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)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 3

Conditions: High-risk Non-muscle Invasive Bladder Cancer

Treatments: Biological: Pembrolizumab; Biological: BCG

Study type: Interventional

Funder types: Industry

Identifiers

NCT03711032

194713 (Other Identifier)

MK-3475-676 (Other Identifier)

3475-676

2018-001967-22 (EudraCT Number)

Details and patient eligibility

About

Researchers are looking for new ways to treat high-risk non muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. High-risk means NMIBC may have a high chance of getting worse or coming back after treatment.

The goals of this study are to learn: 1. If more people who receive pembrolizumab with Bacillus Calmette-Guerin (BCG) have no signs of cancer in their body and live longer without the cancer growing, spreading, or coming back compared to people who receive BCG alone. 2. About the safety and how well people tolerate BCG alone or in combination with pembrolizumab.

Enrollment: 1,405 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,405 participants in 5 patient groups

BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1)

Experimental group

Description:

Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (\~2 years).

Treatment:

Biological: BCG

Biological: Pembrolizumab

BCG Monotherapy: Post-induction Cohort A (Arm A-2)

Experimental group

Description:

Participants receive BCG monotherapy (Induction and Maintenance).

Treatment:

Biological: BCG

BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1)

Experimental group

Description:

Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses (\~1 year).

Treatment:

Biological: BCG

Biological: Pembrolizumab

BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2)

Experimental group

Description:

Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses (\~1 year).

Treatment:

Biological: BCG

Biological: Pembrolizumab

BCG Monotherapy: BCG Naïve Cohort B (Arm B-3)

Experimental group

Description:

Participants receive BCG monotherapy (Induction and Maintenance).

Treatment:

Biological: BCG