Bladder Cancer
Conditions
Keywords
PD1, PDL1, PD-L1, PD-1
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.
Interventions
BIOLOGICALPembrolizumab
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
BIOLOGICALPembrolizumab/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
BIOLOGICALFavezelimab/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
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: Complete Response (CR) Rate of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) | Up to approximately 6 months | 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. |
| Cohort B: 12-month Disease-Free Survival (DFS) Rate of High-Risk NMIBC | Up to approximately 12 months | 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. |
| Cohort A and B: Number of Participants Who Experience an Adverse Event (AE) | Up to approximately 27 months | 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. |
| Cohort A and B: Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A and B: Overall Survival (OS) | Up to approximately 60 months | OS is defined as the time from first dose to death due to any cause. |
| Cohort B: DFS Rate of Any Disease | Up to approximately 60 months | 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. |
| Cohort A: CR Rate of Any Disease | Up to approximately 6 months | 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. |
| Cohort B: 12-month DFS Rate of High-Risk NMIBC in PDL-1 Positive Participants | Up to approximately 12 months | 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. |
| Cohort B: 12-month DFS Rate of Any Disease | Up to approximately 12 months | 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. |
| Cohort A: CR Rate of High-Risk NMIBC in Programmed Cell Death 1 (PDL-1) Positive Participants | Up to approximately 6 months | 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. |
| Cohort A: Duration of Response (DOR) | Up to approximately 60 months | 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. |
| Cohort A and B: Progression-Free Survival (PFS) | Up to approximately 60 months | 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. |
Outcome results
None listed