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) |
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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 event-free survival (EFS) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + Radical Cystectomy [RC]+ Pelvic Lymph Node Dissection [PLND]) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND).
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E.2.2 | Secondary objectives of the trial |
1. To compare pathologic complete response (pCR) rates obtained in+ Arm A (preoperative pembrolizumab + neoadjuvant chemotherapy + RC PLND) and Arm B (preoperative placebo + neoadjuvant chemotherapy + RC + PLND). 2. To compare the overall survival (OS) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND). 3. To assess disease-free survival (DFS) in participants from Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND). 4. To compare the rate of pathologic downstaging (pDS) between Arm A and Arm B. 5. To evaluate the safety and tolerability of pembrolizumab + chemotherapy + RC + PLND. 6. To evaluate changes in patient reported outcomes from baseline and time to deterioration (TTD) using the FACT-BI-Cys instrument and EQ-5D-5L. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for inclusion in this study, the participant must: 1. Have a histologically confirmed diagnosis of UC/MIBC (clinical stage T2 T4aN0M0 or T1 T4aN1M0) with predominant (≥50%) urothelial histology and PD-L1 expression (CPS ≥10 or CPS <10, for PD-L1 CPS score not evaluable refer to inclusion criterion #4) to be confirmed by BICR (central pathology and/or imaging): -T1 disease (eligible only with N1 disease) and T2 disease will be confirmed by central pathology review and T3, T4a, N0 and N1 disease will be confirmed by central imaging review. -Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above. (Participants whose tumors contain predominant [≥50%] plasmacytoid variant are not eligible.) -Participants whose tumors contain any neuroendocrine histology are not eligible. -UCs not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible. 2. Have clinically non-metastatic bladder cancer (N≤1 M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR. 3. Be deemed eligible for RC + PLND by a 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 TUR of a bladder tumor (obtained as early as 60days [+14days] prior to enrollment [providing documented informed consent]) that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression. (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 ECOG performance status of 0 or 1. 6. Have 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 providing documented informed consent. 8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: - Pembrolizumab: 0 days (no requirement) - Gemcitabine and/or cisplatin: 90 days
-Refrain from donating sperm PLUS either: -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) as detailed below: *Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: -Is not a WOCBP OR -Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: - Pembrolizumab: 120 days - Gemcitabine and/or cisplatin: 180 days. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. -A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum) before the first dose of study intervention. -If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. -The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 10. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR. |
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E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant: 1. Has a known additional malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization 2. Has received any prior systemic treatment, chemoradiation, and/or radiation therapy for MIBC or NMIBC. 3. Has ≥N2 disease or metastatic disease (M1) as identified by imaging. 4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria: - Impaired renal function with measured or calculated CrCl <60 mL/min - ECOG Performance Status ≥2 - CTCAE v.4 Grade ≥2 audiometric hearing loss (Audiometric abnormalities without corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for exclusion). 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 or greater heart failure 5. 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 (eg, CTLA-4, OX-40, CD137). 6. Has received prior systemic anticancer therapy including investigational agents within 3 years before randomization. 7. Has received any prior radiotherapy to the bladder. 8. Has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC. 9. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 10. Is currently participating in or has participated in a study of an investigational agent or has 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 intervention. Inhaled or topical steroids are permitted in the absence of autoimmune disease. Physiologic replacement (10 mg/day prednisone equivalent) doses of corticosteroids are permitted for participants with adrenal insufficiency. 12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 16. Has an active infection requiring systemic therapy (IV/oral). Participant may be rescreened once after resolution of the infection. 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 hepatitis B surface antigen [HBsAg] reactive) or known active HCV (defined as detectable HCV RNA via qualitative nucleic acid testing) infection. 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. Has had an allogenic tissue/solid organ transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Event-Free Survival (EFS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 60 months |
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E.5.2 | Secondary end point(s) |
1. Pathologic Complete Response (pCR) Rate 2. Overall Survival (OS) 3. Disease-Free Survival (DFS) 4. Pathologic Downstaging (pDS) Rate 5. Number of Participants Who Experienced an Adverse Event (AE) 6. Number of Participants Who Discontinued Study Treatment Due to an AE 7. Number of Participants Who Experienced Perioperative Complications 8. Change in Patient-Reported Outcomes from Baseline in the Total Score of Functional Assessment of Cancer Therapy – General (FACT-G) 9. Change in Patient-Reported Outcomes from Baseline in the Total Score of FACT-Bladder- (FACT-BI-Cys) 10. Change in Patient-Reported Outcomes from Baseline in FACT-BI-Cys-Trial Outcome Index (TOI) 11. Change in Patient-Reported Outcomes from Baseline in European Quality of Life Questionnaire (EQ-5D-5L) Visual Analog Score (VAS) 12. Time to Deterioration (TTD) in the Total Score of FACT-G 13. TTD in EQ-5D-5L VAS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 60 months 2. Up to approximately 72 months 3. From approximately 20 Weeks to up to approximately 72 months 4. Up to approximately 60 months 5. Up to approximately 72 months 6. Up to approximately 12 months 7. Up to approximately 12 months 8. Up to approximately 72 months 9. Up to approximately 72 months 10. Up to approximately 72 months 11. Up to approximately 72 months 12. Up to approximately 72 months 13. Up to approximately 72 months |
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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 | 6 |
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 |
Ukraine |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Thailand |
Turkey |
United Kingdom |
United States |
Belgium |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Poland |
Spain |
Sweden |
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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
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The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory result or at the time of final contact with the last participant, whichever comes last. |
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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 | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |