Study of Pembrolizumab (MK-3475) and Pembrolizumab With Other Investigational Agents in Participants With High Risk Non-muscle Invasive Bladder Cancer (MK-3475-057/KEYNOTE-057)

Study Overview
=================
Brief Summary
-----------------
In this study, participants with high risk non-muscle-invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette Guerin (BCG) therapy and who are considered ineligible for or have refused to undergo radical cystectomy, will receive pembrolizumab therapy or pembrolizumab in combination with other investigational agents. The primary study hypothesis is that treatment with pembrolizumab will result in a clinically meaningful response.

Official Title
-----------------
A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) and Pembrolizumab in Combination With Other Investigational Agents in Subjects With High Risk Non-muscle-Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

Conditions
-----------------
Bladder Cancer

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Biological: Pembrolizumab/vibostolimab coformulation
* Biological: Favezelimab/pembrolizumab coformulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, high grade Ta and / or carcinoma in situ [CIS]) transitional cell carcinoma of the bladder (mixed histology tumors allowed if transitional cell histology is predominant histology). Fully resected disease at study entry (residual CIS acceptable) BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy Ineligible for radical cystectomy or refusal of radical cystectomy Available tissue from a newly obtained core biopsy of a tumor lesion not previously irradiated Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Adequate organ function Female participants of childbearing potential have a negative urine or serum pregnancy test and must be willing to use an adequate method of contraception Male participants must be willing to use an adequate method of contraception Exclusion criteria: Centrally assessed muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and / or stage IV) Centrally assessed concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium Currently participating or has participated in a study of an investigational agent and received study therapy or received investigational device within 4 weeks prior to the first dose of study treatment Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy / Transurethral Resection of Bladder Tumor (TURBT) to starting study treatment Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤7 and prostatic-specific antigen (PSA) undetectable for at least 1 year while off androgen deprivation therapy that was either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation Active autoimmune disease that has required systemic treatment in the past 2 years Evidence of interstitial lung disease or active non-infectious pneumonitis Active infection requiring systemic therapy Pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial through 120 days after the last dose of study treatment Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor Known human immunodeficiency virus (HIV) Known active Hepatitis B or C infection Received a live virus vaccine within 30 days of planned start of study treatment Has had an allogeneic tissue/solid organ transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants receive pembrolizumab, 200 mg, intravenously, every 3 weeks (Q3W) for up to 24 months. | Biological: Pembrolizumab<br>* Participants receive pembrolizumab 200mg via IV infusion once every 3 weeks for up to 35 administrations<br>* Other names: KEYTRUDA;|
| Experimental: Pembrolizumab coformulation<br>Participants receive either pembrolizumab/vibostolimab or favezelimab/pembrolizumab coformulation intravenously Q3W for up to 24 months | Biological: Pembrolizumab/vibostolimab coformulation<br>* Participants receive pembrolizumab/vibostolimab (coformulation of 200 mg pembrolizumab and 200 mg vibostolimab) via IV infusion once every 3 weeks for up to 35 administrations<br>* Other names: MK-7684A;Biological: Favezelimab/pembrolizumab coformulation<br>* Participants receive favezelimab/pembrolizumab (coformulation of 800mg favezelimab and 200 mg pembrolizumab) via IV infusion once every 3 weeks for up to 35 administrations<br>* Other names: MK-4280A;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate |  | Up to 3 years | 
| Disease Free Survival Rate |  | Up to approximately 12 months | 
| 12-month Complete Response Rate |  | Up to approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response |  | Up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PD1, PDL1, PD-L1, PD-1