| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle Invasive Bladder Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Muscle Invasive Bladder Cancer |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005003 |
| E.1.2 | Term | Bladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab + neoadjuvant chemotherapy + Radical Cystectomy (RC) + Pelvic Lymph Node Dissection [PLND]) and Arm B (preoperative placebo + neoadjuvant chemotherapy + RC+ PLND), based on central pathology review, in participants whose tumors express programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥10 and in all participants, irrespective of CPS score.
2. To compare event-free survival (EFS) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND), evaluated in participants whose tumors express PD-L1 CPS ≥10 and in all participants, irrespective of CPS score.
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| E.2.2 | Secondary objectives of the trial |
1. To compare the overall survival (OS) between Arm A and Arm B, evaluated in participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
2. To assess disease-free survival (DFS) in participants from Arm A and Arm B, who are disease free after surgery based on participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
3. To compare the rate of pathologic downstaging (pDS) between Arm A and Arm B, evaluated in participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
4. To evaluate the safety and tolerability of pembrolizumab + chemotherapy + RC + PLND. |
|
| 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 and/or tissue and/or others 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. |
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| E.3 | Principal inclusion criteria |
To be eligible for inclusion in this study, the participant must:
1. Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR):
- Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above.
- Participants whose tumors contain any neuroendocrine component are not eligible.
- Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
2. Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR.
3. Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
4. Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to enrollment [ICF signed]) that is submitted and adequate to determine histology, muscle invasion, and PD-L1 status by central pathology vendor. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification.
5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Have demonstrated adequate organ function (all screening labs should be performed within 14 days prior to randomization).
7. Participant is male or female and at least 18 years of age inclusive, at the time of signing the informed consent.
8. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus an additional 90 days [a spermatogenesis cycle] for study treatments where there is risk of clinically relevant genotoxicity) after the last dose of study treatment and refrain from donating sperm during this period.
9. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. WOCBP who agrees to follow the contraceptive guidance:Contraceptive Guidance and Pregnancy Testing during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus 30 days [a menstruation cycle] for study treatments with risk of genotoxicity) after the last dose of study treatment.
10. 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. |
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| E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active anti-cancer treatment ≤3years of study randomization
2. Has received any prior systemic anti-neoplastic treatment for MIBC.
3. Has an abdomino-pelvic lymph node ≥15 mm in the short axis.
4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria:
- Impaired renal function with measured or calculated creatinine clearance (CrCl) <60 mL/min (calculated by Cockcroft-Gault method or 24-hour urine collection).
- ECOG Performance Status ≥ 2
- CTCAE v.4 Grade ≥2 audiometric hearing loss (threshold shift of >25 dB averaged at 2 consecutive test frequencies in at least 1 ear; testing is not required at screening; it may be performed at investigator’s discretion)
- CTCAE v.4 Grade ≥2 peripheral neuropathy
- New York Heart Association (NYHA) Class III heart failure
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 therapy with hematopoietic growth factor such as granulocyte-colony stimulating factor (G-CSF) or GM-CSF in 14 days prior to randomization.
7. Has received prior systemic anti-cancer therapy including investigational agents within 3 years of randomization.
8. Has received any prior radiotherapy to the bladder.
9. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, 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.
10. Is currently participating in or has participated in a study of an investigational agent orhas used an investigational device within 4 weeks prior to the first dose of study intervention.
11. 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 the first dose of study drug.
12. Has hypersensitivity to mAbs (including pembrolizumab) and/or any of their excipients.
13. Has severe hypersensitivity (≥Grade 3) to cisplatin and/or gemcitabine and any of their excipients.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection.
17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
19. 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.
20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study intervention.
22. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Pathologic Complete Response Rate in All Participants
2. Pathologic Complete Response Rate in Participants Whose Tumors Express PD-L1, CPS ≥10
3. Event-Free Survival in All Participants
4. Event-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 months (Time of surgery)
2. Up to approximately 4 months (Time of surgery)
3. Up to approximately 5.5 years
4. Up to approximately 5.5 years |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival in All Participants
2. Overall Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
3. Disease-Free Survival in All Participants
4. Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
5. Pathologic Downstaging Rate in All Participants
6. Pathologic Downstaging Rate in Participants Whose Tumors Express PD- L1, CPS ≥10
7. Percentage of Participants Experiencing Adverse Events (AEs)
8. Percentage of Participants Discontinuing Study Drug Due to an AE
9. Percentage of Participants Experiencing Perioperative Complications
10. Change in Patient-Reported Outcomes from Baseline in the Total Score of Functional Assessment of Cancer Therapy – General (FACT-G)
11. Change in Patient-Reported Outcomes from Baseline in the Total Score FACT B1-Cys
12. Change in Patient-Reported Outcomes from Baseline in FACT-B1-Cys-Trial Outcome Index (TOI)
13. Change in Patient-Reported Outcomes from Baseline in EQ-5D-5L Visual Analog Score (VAS)
14. Change in Patient-Reported Outcomes from Baseline in EQ-5D-5L Utility Score
15. Time to Deterioration (TTD) in FACT-G
16. Time to Deterioration in EQ-5D-5L VAS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5.5 years
2. Up to approximately 5.5 years
3. From approximately 5 months up to approximately5.5 years
4. From approximately 5 months up to approximately5.5 years
5. Up to approximately 4 months (Time of surgery)
6. Up to approximately 4 months (Time of surgery)
7. Up to approximately 5.5 years
8. Up to approximately 1 year
9. Up to approximately 1 year
10. Up to approximately 5.5 years
11. Up to approximately 5.5 years
12. Up to approximately 5.5 years
13. Up to approximately 5.5 years
14. Up to approximately 5.5 years
15. Up to approximately 5.5 years
16. Up to approximately 5.5 years
|
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Thailand |
| Turkey |
| Ukraine |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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