| 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 |
Cohort A
To compare the CRR for the combination of pembrolizumab + BCG versus BCG alone in participants with CIS.
Cohort B
- To compare the EFS between participants who receive pembrolizumab + BCG (reduced maintenance) versus BCG alone
- To compare the EFS between participants who receive pembrolizumab
+ BCG (full maintenance) versus BCG alone |
|
| E.2.2 | Secondary objectives of the trial |
Cohort A
-EFS between pembrolizumab+BCG vs BCG alone
-RFS, OS, DSS, time to cystectomy between pembrolizumab+BCG vs BCG -12-mo EFS rate, DOR, 12-mo DOR rate in pembrolizumab+BCG vs BCG
-safety and tolerability of pembrolizumab+BCG
-changes from baseline and TTD in HRQoL scores in both groups, using EORTCQLQC30,EuroQoL-EQ-5D-5L,EORTC QLQ-NMIBC24.
Cohort B
-CRR for pembrolizumab+BCG (reduced/full maintenance) vs BCG in participants with CIS
-RFS, OS, DSS, time to cystectomy between pembrolizumab+BCG (reduced/full maintenance) and BCG
-DOR and 12-mo DOR rate in participants with CIS who receive pembrolizumab+BCG (reduced maintenance), pembrolizumab+BCG (full maintenance) and BCG
-24-mo EFS rate in participants who receive pembrolizumab+BCG (reduced maintenance), pembrolizumab+BCG (full maintenance) and BCG
-changes from baseline and TTD in HRQoL scores in all groups, using EORTC QLQC30, EuroQoL EQ-5D-5L,EORTC QLQ-NMIBC24
-safety and tolerability of pembrolizumab + BCG |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort A-BCG Post-induction Cohort
1. Male/female participants who are at least 18 years of age on the day of providing documented informed consent will be enrolled in this study
2. Have locally and BICR-confirmed histological diagnosis of high-risk non-muscle invasive (T1, highgrade Ta and/or CIS) UC 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
4. Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC
5. Have undergone cystoscopy/TURBT to remove all resectable disease within 12 weeks prior to randomization
6. Have provided tissue for biomarker analysis from the most recent TURBT/biopsy procedures from which tumor sample is available
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. Male participants are eligible to participate if they agree to the following during the treatment period and for at least 7 days after the last dose of BCG:
•Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
•Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
a) Is not a WOCBP
OR
b) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a longterm and persistent basis), during the treatment period and for at least 7 days after the last dose of BCG or 120 days after the last dose of pembrolizumab, whichever comes last
11. The participant (or legally acceptable representative) provides documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the main study without participating in FBR Cohort B-BCG Naïve Cohort
12. Male/female participants who are at least 18 years of age on the day of providing documented informed consent will be enrolled in this study
13. Have locally and BICR-confirmed histological diagnosis of high-risk non-muscle invasive (T1, highgrade Ta and/or CIS) UC of the bladder
14. Have undergone cystoscopy/TURBT to remove all resectable disease within 12 weeks prior to randomization
15. Have provided tissue for biomarker analysis from the most recent TURBT/biopsy procedures from which tumor sample is available
16. Have a performance status of 0, 1 or 2 on the ECOG performance Scale, as assessed within 14 days prior to randomization
17. Have adequate organ function. Specimens must be collected within 14 days prior to randomization
18. Male participants are eligible to participate if they agree to the following during the treatment period and for at least 7 days after the last dose of BCG lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
•Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
19. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
a) Is not a WOCBP
OR
b) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a longterm and persistent basis), during the treatment period and for at least 7 days after the last dose of BCG or 120 days after the last dose of pembrolizumab, whichever comes last
20. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the main study without participating in FBR |
|
| E.4 | Principal exclusion criteria |
Cohort A-BCG Post-induction Cohort
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 of or concurrent locally advanced non-resectable (ie, T2, T3, T4) or metastatic UC
3. Has concurrent extra-vesical non-muscle invasive urothelial carcinoma, concurrent upper tract involvement, or invasive prostatic UC including T1 or greater disease, or ductal invasion
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2
agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
5. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment
6. Has received prior radiotherapy within 2 weeks of start of study treatment
7. Has received a live vaccine within 30 days of start of study treatment
8. 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
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within
7 days of start of study treatment
10. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
11. Has hypersensitivity to pembrolizumab and/or any of its excipients
12. Has an active autoimmune disease that has required systemic treatment in past 2 years
13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
14. Has 1 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
15. Has an active infection or diagnosis requiring systemic antimicrobial therapy
16. Has a known history of HIV infection
17. Has a known history of Hepatitis B or known active Hepatitis C virus infection
18. Has current active tuberculosis
19. Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study
20. Has had an allogenic-tissue/solid organ transplant
21. Has any contraindication(s) to IV contrast or is otherwise unable to have screening imaging with IV contrast performed
22. Has a history of or concurrent locally advanced or metastatic UC
23.Has concurrent extra-vesical non-muscle invasive UC or a history of extra-vesical non-muscle invasive UC that recurred within 2 years prior.
24. Has any contraindication(s) to IV contrast or is otherwise unable to have screening imaging with IV contrast performed
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
26. Has received any prior treatment with BCG for their NMIBC within the past 2 years prior to study entry
27. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment
28. Has received prior radiotherapy within 2 weeks of start of study treatment
29. Has received a live vaccine within 30 days of start of study treatment
30. 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
31. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of start of study treatment
32. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
33. Has hypersensitivity to pembrolizumab and/or any of its excipients
34. Has an active autoimmune disease that has required systemic treatment in past 2 years
35. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
36. 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
37. Has an active infection or diagnosis requiring systemic antimicrobial therapy
38. Has a known history of HIV infection.
39. Has a known history of Hepatitis B or known active Hepatitis C virus infection
40. Has current active tuberculosis
41. Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study 42. Has had an allogenic-tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohort A:
Complete response among CIS participants
Cohort B:
Event-free survival (EFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint (CRR) analysis for Cohort A will be performed when enrollment is complete and all participants are evaluable for the primary endpoint which is projected to occur approximately 65 months after study start.
The final analysis of the primary endpoint (EFS) for Cohort B is event driven and will be conducted after approximately 203 EFS events have been observed in Arm B-1+Arm B-3 and 203 EFS events in Arm B-2+Arm B-3 which is projected to occur approximately 56 months after study start.
|
|
| E.5.2 | Secondary end point(s) |
English Cohort A:
EFS
Cohort B:
None |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final EFS analysis for Cohort A is event driven and will be conducted after approximately 282 Event Free Survival events have been observed which is projected to occur approximately 65 months after study start. |
|
| 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 | 5 |
| 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 | 59 |
| 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 |
| Colombia |
| Costa Rica |
| Guatemala |
| Peru |
| Puerto Rico |
| Turkey |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Finland |
| Germany |
| Greece |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Switzerland |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
| France |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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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