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)

Bladder Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02625961
• Other study ID #: 3475-057
• Secondary ID: 1632362022-50252
• Status: Recruiting
• Phase: Phase 2
• Start date: February 10, 2016
• Est. completion date: August 31, 2030

Study information

• Verified date: April 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 320
• Est. completion date: August 31, 2030
• Est. primary completion date: August 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Biological:
• Pembrolizumab
Participants with CIS with or without papillary tumors (Cohort A) and participants with papillary tumors only, without CIS (Cohort B) receive pembrolizumab 200mg via IV infusion once every 3 weeks for up to 35 administrations
• Pembrolizumab/vibostolimab coformulation
Participants with CIS with or without papillary tumors (Cohort C) receive pembrolizumab/vibostolimab (coformulation of 200 mg pembrolizumab and 200 mg vibostolimab) via IV infusion once every 3 weeks for up to 35 administrations
• Favezelimab/pembrolizumab coformulation
Participants with CIS with or without papillary tumors (Cohort C) receive favezelimab/pembrolizumab (coformulation of 800mg favezelimab and 200 mg pembrolizumab) via IV infusion once every 3 weeks for up to 35 administrations

Locations

Country	Name	City	State
Brazil	MSD Brasil	Sao Paulo
Canada	Merck Canada	Kirkland	Quebec
Finland	MSD Finland Oy	Espoo
France	MSD France	Paris
Italy	MSD Italia S.r.l.	Rome
Netherlands	Merck Sharp & Dohme BV	Haarlem
Puerto Rico	Call for Information (Investigational Site 2402)	Ponce
Puerto Rico	Call for Information (Investigational Site 2400)	Rio Piedras
Singapore	Merck Sharp & Dohme (I.A.) Corp	Singapore
Spain	Merck Sharp and Dohme de Espana S.A.	Madrid
Turkey	Merck Sharp & Dohme Ilaclari Ltd. Sti	Istanbul
United States	Call for Information (Investigational Site 0074)	Bala-Cynwyd	Pennsylvania
United States	Call for Information (Investigational Site 0085)	Chicago	Illinois
United States	Call for Information (Investigational Site 0072)	Cincinnati	Ohio
United States	Call for Information (Investigational Site 0009)	Cleveland	Ohio
United States	Call for Information (Investigational Site 0002)	Hackensack	New Jersey
United States	Call for Information (Investigational Site 0080)	Houston	Texas
United States	Call for Information (Investigational Site 0084)	Indianapolis	Indiana
United States	Call for Information (Investigational Site 0023)	Minneapolis	Minnesota
United States	Call for Information (Investigational Site 0078)	Myrtle Beach	South Carolina
United States	Call for Information (Investigational Site 0018)	New Brunswick	New Jersey
United States	Call for Information (Investigational Site 0004)	New York	New York
United States	Call for Information (Investigational Site 0021)	Orange	California
United States	Call for Information (Investigational Site 0081)	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Finland,  France,  Italy,  Netherlands,  Puerto Rico,  Singapore,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort A: Complete Response (CR) Rate of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC)	The CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review.	Up to approximately 6 months
Primary	Cohort B: 12-month Disease-Free Survival (DFS) Rate of High-Risk NMIBC	DFS of high-risk NMIBC is defined as the time from the first dose to the first occurrence of high-risk NMIBC or worse per central pathology and radiology review. The 12-month DFS rate is the percentage of participants remaining free from high-risk NMIBC or worse at 12 months.	Up to approximately 12 months
Primary	Cohort C: 12-month CR Rate of High-Risk NMIBC	The 12-month CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 12 months.	Up to approximately 12 months
Primary	All Cohorts: Number of Participants Who Experience an Adverse Event (AE)	An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.	Up to approximately 27 months
Primary	All Cohorts: Number of Participants Who Discontinue Study Treatment Due to an AE	An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.	Up to approximately 24 months
Secondary	Cohort A: CR Rate of Any Disease	The CR rate of any disease is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of any disease or worse per central pathology and radiology review.	Up to approximately 6 months
Secondary	Cohort C: CR Rate of High-Risk NMIBC at 3 Months	The CR rate of high-risk NMIBC at 3 months is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 3 months.	Up to approximately 3 months
Secondary	Cohort C: CR Rate of High-Risk NMIBC at 6 Months	The CR rate of high-risk NMIBC at 6 months is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 6 months.	Up to approximately 6 months
Secondary	Cohort C: Overall CR Rate of High-Risk NMIBC	The overall CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at first evaluable efficacy assessment.	Up to approximately 6 months
Secondary	Cohort A: CR Rate of High-Risk NMIBC in Programmed Cell Death 1 (PDL-1) Positive Participants	The CR of high-risk NMIBC is defined as the proportion of PDL-1 positive participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review.	Up to approximately 6 months
Secondary	Cohort A and C: Duration of Response (DOR)	The DOR is defined as the time from the first documented evidence of CR until the recurrence of disease or worse per clinical pathology and radiology review.	Up to approximately 60 months
Secondary	All Cohorts: Progression-Free Survival (PFS)	PFS is defined as the time from the first dose to progression to worsening of grade or stage or death or to muscle invasive or metastatic disease or death per central urology, pathology, and radiology review.	Up to approximately 60 months
Secondary	All Cohorts: Overall Survival (OS)	OS is defined as the time from first dose to death due to any cause.	Up to approximately 60 months
Secondary	Cohort B: DFS Rate of Any Disease	DFS of any disease is defined as the time from the first dose to the first occurrence of any disease or worse per central pathology and radiology review. The DFS rate is the percentage of participants remaining free of any disease or worse.	Up to approximately 60 months
Secondary	Cohort B: 12-month DFS Rate of Any Disease	DFS of any disease is defined as the time from the first dose to the first occurrence of any disease or worse per central pathology and radiology review. The 12-month DFS rate of any disease is the percentage of participants remaining free of any disease or worse at 12 months.	Up to approximately 12 months
Secondary	Cohort B: 12-month DFS Rate of High-Risk NMIBC in PDL-1 Positive Participants	DFS of high-risk NMIBC is defined as the time from the first dose to the first occurrence of high-risk NMIBC or worse per central pathology and radiology review. The 12-month DFS rate is the percentage of participants remaining free from high-risk NMIBC or worse at 12 months. The 12-month DFS rate of high-risk NMIBC in PDL-1 positive participants will be reported.	Up to approximately 12 months

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary