Non-Muscle Invasive Bladder Cancer (NMIBC) MedDRA version: 20.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have a histologically-confirmed diagnosis of high risk non-muscleinvasive (T1, High Grade Ta and/or CIS) transitional cell carcinoma of the bladder. 2. In subjects who have papillary tumors (Ta and T1), a complete TURBT must have been performed, as characterized by: -Attainment of a visually complete resection of all papillary tumors (Ta and T1) -Residual CIS not amenable to complete resection is allowed -The most recent cystoscopy/TURBT must have been performed within 12 weeks of randomization -For Cohort C: subjects with T1 disease should have undergone a restaging TURBT procedure within 12 weeks prior to randomization to confirm complete resection. 3. Have been treated with adequate BCG therapy and have developed high risk NMIBC that is unresponsive to BCG therapy. 4. Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating surgeon. 5. Have provided tissue for biomarker analysis from the most recent cystoscopy/TURBT procedures from which tumor sample is available. 6. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. (Max of 5% ECOG of 2.) (for cohorts A and B only) 7. Have adequate organ function. 8. A female participant is eligible if not pregnant or breastfeeding, and at least one of the following applies: - Is not a WOCBP; or - Is a WOCBP and using a contraceptive method as described in the protocol. A WOCBP must have a negative pregnancy test as described in the protocol Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 106 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 214
Exclusion criteria
Exclusion criteria: 1 . Has centrally-assessed muscle invasive (i.e. T2, T3, T4) locally advanced nonresectable or metastatic urothelial carcinoma. 2 . Has centrally-assessed concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium. 3 . Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 4 . Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of the most recent cystoscopy/TURBT to starting trial treatment. 5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or who has not recovered (ie, = Grade 1 or at baseline) from adverse events due to a previously administered agent. 6. Has a known additional malignancy that has had progression or has required active treatment in the last three years 7. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before randomization/study allocation for Cohort C. 8. Has severe hypersensitivity to pembrolizumab (all cohorts), MK-7684A (Cohort C arm 1), MK-4280A (Cohort C Arm 2), and/or any of their excipients. 9. Has an active autoimmune disease that has required systemic treatment in past 2 years 10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study intervention. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 11. Has a history of (non-infectious) pneumonitis/or interstitial lung disease that required steroids or has current pneumonitis. 12. Has an active infection requiring systemic therapy, including active or intractable UTI in the last month. 13. Has a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation, or is not in the best interest of the subject to participate, in the opinion of the investigator. 14. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the trial. 15. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL2 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137). 17. Has received previous treatment with another agent targeting the TIGIT and/or LAG3 receptor pathway (Cohort C only). 18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV- 1/2 antibodies). 19. Has known active Hepatitis B or Hepatitis C. 20. Has received a live virus vaccine within 30 days of planned start of trial treatment. 21. Has had an allogeneic tissue/solid organ transplant.
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Cohort A and C: CR rate of any disease in the overall population; DOR of high risk NMIBC and any disease. Cohort B: 12-month DFS rate of any disease in the overall population. ;Timepoint(s) of evaluation of this end point: Interim Analysis Proof of Concept (IA POC) = 20 Cohort A subjects @ 12 weeks Interim Analysis II (IA 2) = 50 Cohort A subjects @ 24 weeks Final Analysis = Full Enrollment plus 9 months | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: In: Cohort A – Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS) And Cohort B – Subjects without CIS at baseline (High Grade Ta or Any Grade T1) And Cohort C - Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS) The study is considered to have met its primary objective if the primary hypothesis for either Cohort A or Cohort B is successful. To evaluate anti-tumor activity of pembrolizumab (MK-3475) by evaluating the absence of high risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review. To evaluate anti-tumor activity of MK-7684A and MK-4280 by 12-month complete response (CR) rate of high-risk NMIBC, as determined by cystoscopy, cytology, biopsy and radiologic imaging by central pathology and radiology review. ;Secondary Objective: Evaluate anti-tumor activity of MK-3475: Cohort A -CIS at baseline - CR rate of any disease - DOR of high risk NMIBC and any disease (resp only) - in PD-L1+ subjects by CR rate of high risk NMIBC and any disease - in PD-L1+ subjects by DOR of high risk NMIBC and any disease (resp only) - in the study population and in PD-L1+ subjects by: a. DOR rate at specific time points of both high risk NMIBC and any disease (resp only) Cohort B -no CIS at baseline - DFS rate of any disease - in PD-L1 + subjects by 12-month DFS rate of high risk NMIBC and any disease - in the study population and in PD-L1+ subjects by: a. Overall DFS and 3-month/6-month DFS rates of high risk NMIBC and any disease Cohort C - CIS at baseline - DOR of high-risk NMIBC (responders only) - CR rate at 3 months, CR rates at 6 months, overall CR rate All cohorts: - PFS, to worsening of grade or stage or death - PFS, to muscle-invasive or metastatic disease or death; or - OS ;Primary end point(s): Cohort A and C: CR rate of high risk NMIBC in the overall population. Cohort B: 12-month DFS rate of high risk NMIBC in the overall pop | — |
Countries
Australia, Brazil, Canada, Finland, France, Greece, Italy, Japan, Korea, Republic of, Netherlands, Puerto Rico, Russian Federation, Singapore, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactGlobal Clinical Trials Operations
Merck Sharp & Dohme LLC
Outcome results
None listed