Clinical trial NCT02625961: 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)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Bladder Cancer
Keywords: PD1
PDL1
PD-L1
PD-1
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-12-09
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Effective as of Amendment 12, Cohort C was made exploratory, and all Cohort C outcome measures were made exploratory.

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

Primary outcomes:
measure: Cohort A: Complete Response (CR) Rate of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC)
timeFrame: Up to approximately 6 months
measure: Cohort B: 12-month Disease-Free Survival (DFS) Rate of High-Risk NMIBC
timeFrame: Up to approximately 12 months
measure: Cohort A and B: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to approximately 27 months
measure: Cohort A and B: Number of Participants Who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 24 months
Secondary outcomes:
measure: Cohort A: CR Rate of Any Disease
timeFrame: Up to approximately 6 months
measure: Cohort A: CR Rate of High-Risk NMIBC in Programmed Cell Death 1 (PDL-1) Positive Participants
timeFrame: Up to approximately 6 months
measure: Cohort A: Duration of Response (DOR)
timeFrame: Up to approximately 60 months
measure: Cohort A and B: Progression-Free Survival (PFS)
timeFrame: Up to approximately 60 months
measure: Cohort A and B: Overall Survival (OS)
timeFrame: Up to approximately 60 months
measure: Cohort B: DFS Rate of Any Disease
timeFrame: Up to approximately 60 months
measure: Cohort B: 12-month DFS Rate of Any Disease
timeFrame: Up to approximately 12 months
measure: Cohort B: 12-month DFS Rate of High-Risk NMIBC in PDL-1 Positive Participants
timeFrame: Up to approximately 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguie M, Krieger LEM, Singer EA, Bajorin DF, Grivas P, Seo HK, Nishiyama H, Konety BR, Li H, Nam K, Kapadia E, Frenkl T, de Wit R. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930. doi: 10.1016/S1470-2045(21)00147-9. Epub 2021 May 26.