| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk Non-muscle Invasive Bladder Cancer (NMIBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| High Risk Non-muscle invasive bladder cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022877 |
| E.1.2 | Term | Invasive bladder cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the complete response rate (CRR) for the combination of pembrolizumab + Bacillus Calmette-Guerin (BCG) versus BCG alone in participants with carcinoma in situ (CIS) |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare the event-free survival (EFS) between participants who receive pembrolizumab + BCG and BCG alone
2) To compare the following endpoints between participants who receive pembrolizumab + BCG and BCG alone:
a. Recurrence-free survival (RFS)
b. Overall survival (OS)
c. Disease-specific survival (DSS)
d.Time to cystectomy
3) To assess the following endpoints in participants who receive pembrolizumab + BCG and BCG alone:
a. 12-month EFS rate
b. Duration of response (DOR)
c. 12-month DOR rate
4) To determine the safety and tolerability of pembrolizumab + BCG
5) To evaluate changes from baseline and time to deterioration (TTD) in HRQoL scores in both treatment groups, using two general instruments (European Organisation for Research and Treatment of Cancer [EORTC] QoL questionnaire-Core 30 [QLQ-C30], and European Quality of Life [EuroQoL]-5 Dimensions, 5-level Questionnaire [EQ-5D-5L]) and one disease-specific instrument EORTC QLQ-NMIBC24. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (Blood, plasma, serum, urine and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. Male/female participants who are at least 18 years of age on the day of signing informed consent will be enrolled in this study
2. Have histologically confirmed by BICR diagnosis of high-risk non-muscle invasive (T1, highgrade Ta and/or CIS) TCC of the bladder
3. Have been treated with one adequate course of BCG induction therapy for the treatment of HR NMIBC defined as at least 5 intravesical instillations of BCG within a 10 week period of time. If more than one induction course or any maintenance therapy of BCG has been received, the participant is not eligible for this study
4. Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC defined as:
a. HR NMIBC: recurrent T1, high-grade Ta and/or CIS
b. Persistent: remains present within 3 months (-2 weeks) to 6 months (+4 weeks) after start of BCG induction, or
c. Recurrent: reappearance of high-risk NMIBC after achieving a CR or tumorfree state within 6 months (+ 4 weeks) after start of BCG induction. The recurrence must be within 24 months of last exposure to BCG (with up to an additional 56 days allowed to account for delays in the 24 month assessment)
5. Have undergone cystoscopy/TURBT to remove all resectable disease within 12 weeks prior to randomization. Participants with recurrent T1 disease should have undergone a restaging TURBT procedure between 14 to 56 days prior to randomization to confirm complete resection and that the participant continues to meet eligibility criteria.
-If restaging TURBT is performed between 14 to 56 days prior to randomization and the absence of muscle invasive tumor (≥T2) is confirmed by central pathology review, participants are still eligible even if first TURBT was performed >12 weeks prior to randomization.
- Tissue resected during restaging TURBT must be sent to central pathology lab for tumor histology evaluation with results confirming eligibility prior to randomization.
6. Have provided tissue for biomarker analysis from the most recent TURBT/biopsy procedures from which tumor sample is available. The PD-L1 status of the archived or recently-obtained biopsy specimen must be determined by the central laboratory prior to randomization. If submitting unstained cut slides, freshly cut slides should be submitted
7. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed within 14 days prior to randomization
8. Have adequate organ function. Specimens must be collected within 14 days prior to randomization
9. A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a) Not a WOCBP
OR
b) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
11. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However the participant may participate in the main study without participating in future biomedical research |
|
| E.4 | Principal exclusion criteria |
1. Has persistent (remains present or occurs within 3 months (-2 weeks) to 6 months (+4 weeks) after start of BCG induction) T1 disease following an induction course of BCG
2. Has a history or concurrent muscle invasive (ie, T2, T3, T4), locally advanced non-resectable or metastatic UC.
3. Has concurrent extra-vesical (ie, urethra, ureter, renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, concurrent upper tract involvement, or invasive prostatic TCC including T1 or greater disease, or ductal invasion
4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
6. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment
7. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
8. Has received a live vaccine within 30 days of start of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus Calmette Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of start of study treatment
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 of start of study treatment
11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
12. Has hypersensitivity to pembrolizumab and/or any of its excipients
13. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
15. Has one or more of the following contraindications to BCG: prior BCG sepsis or systemic infection, total bladder incontinence, or an adverse experience to a previous BCG instillation that resulted in treatment discontinuation and precludes retreating with BCG
16. Has an active infection requiring systemic therapy (including a symptomatic UTI)
17. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority
18. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
19. Has current active tuberculosis. Assessment method(s) may include:
-Tuberculin Skin Test (TST) with confirmatory chest X-ray if TST positive,
or
-Interferon Gamma Release Assay (IGRA) may be used in place of the TST, or
-Alternative testing may also be used as allowed by local regulations/standard of care.
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
21. Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study
22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.
23. Has had an allogenic-tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete response among CIS participants |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint (CRR) analysis will be performed when the enrollment is complete and all participants have had the opportunity for a 12 week assessment of CR which is projected to occur approximately 36 months after study start |
|
| E.5.2 | Secondary end point(s) |
| Event-free survival (EFS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis of this study is event driven and will be conducted after approximately 304 Event Free Survival events have been observed |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient Reported Outcomes |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Finland |
| Germany |
| Greece |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Netherlands |
| Norway |
| Peru |
| Poland |
| Portugal |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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