| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle-invasive Bladder Cancer (MIBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Participants with muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based chemotherapy |
|
| 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 |
1. To compare pathologic complete response (pCR) rates between Arm A
(preoperative pembrolizumab and radical cystectomy plus pelvic lymph
node dissection [RC+PLND]) and Arm B (RC+PLND) and between Arm C
(preoperative enfortumab vedotin in combination with pembrolizumab
and RC+PLND) and Arm B, based on central pathologic review, evaluated
in participants whose tumors express PD-L1 CPS ≥10 and all
participants, irrespective of CPS.
2. To compare EFS between Arm A (perioperative pembrolizumab and
RC+PLND) and Arm B (RC+PLND) and between Arm C (perioperative
enfortumab vedotin in combination with pembrolizumab and RC+PLND)
and Arm B, evaluated in participants whose tumors express PD-L1 CPS ≥
10 and all participants, irrespective of CPS. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare OS between Arm A (perioperative pembrolizumab and
RC+PLND) and Arm B (RC+PLND) and between Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and RC+PLND)
and Arm B, evaluated in individuals whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS.
2. To assess DFS in participants from Arm A (perioperative pembrolizumab and RC+PLND), Arm B (RC+PLND), and Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and RC+PLND) who are disease free after surgery based on participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS.
3. To compare the rates of pDS between Arm A and Arm B and between Arm C and Arm B, evaluated in participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS.
4. To evaluate the safety and tolerability of perioperative pembrolizumab with RC+PLND and perioperative enfortumab vedotin in combination with pembrolizumab with RC+PLND. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Have a histologically confirmed diagnosis of MIBC cT2-T4aN0M0 or cT1-T4aN1M0 with predominant (≥50%) urothelial histology (pathologic
stage pT2-T4a tumors or pT1 [only if N1] to be confirmed by BICR).
*Participants whose tumors are pT1 are eligible only with N1 disease
(N1 will be confirmed by BICR)
*Participants with mixed histology are eligible provided the urothelial
component is ≥50%
*Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible
*Participants whose tumors show any one of the following variant histologies, plasmacytoid, clear cell, lipid rich, giant cell, sarcomatoid
and/or neuroendocrine component are not eligible (variant histology to be confirmed locally).
-Have clinically non-metastatic bladder cancer (N≤1M0) determined by
imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR
-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
-Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
*Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
*ECOG Performance Status 2
*CTCAE v.4 Grade ≥2 audiometric hearing loss
*NYHA Class III heart failure
-Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days [+ 14 days] prior to study enrollment [ICF signed]) that is submitted and adequate to determine pathologic stage pT2-T4a or pT1 (only if N1 confirmed by BICR), urothelial histology, 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. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
-Must have an ECOG performance status of 0, 1, or 2
-Demonstrate adequate organ function (all screening labs should be performed within 14 days prior to randomization)
-Participant is male or female at least 18 years of age, at the time of signing the informed consent
-Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days after the last dose of enfortumab vedotin:
*Refrain from donating sperm
PLUS:
*Must agree to use contraception unless confirmed to be azoospermic. If the male participants are receiving pembrolizumab only or undergoing surgery only, there are no contraception requirements
*Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical
studies.
-A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least 1 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 120 days after the last dose of pembrolizumab and 60 days after the last dose of enfortumab vedotin, whichever comes last, 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 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 within 24 hours before the first dose of study intervention.
*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.
*Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
-The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. |
|
| E.4 | Principal exclusion criteria |
-Has a known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization.
-Participants with ≥ N2 or M1 disease
-Has received any prior systemic antineoplastic treatment for MIBC.
-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).
-Has received prior systemic anticancer therapy including investigational agents (including enfortumab vedotin or other MMAE-based ADCs) within 3 years prior to randomization.
-Has received any prior radiotherapy to the bladder.
-Has received a partial cystectomy of the bladder to remove any NMIBC
or MIBC.
-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, 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
-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
-Has ongoing sensory or motor neuropathy Grade 2 or higher
-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. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency
-Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
-Has known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
-Has active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator
-Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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
-Has a history of uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated
diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
-Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
-Has an active infection (viral, bacterial, or fungal) requiring systemic therapy. Participants may be rescreened once after resolution of the
infection
-Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
-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
-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
-Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
-Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Pathological Complete Response (pCR) Rate in All Participants
2. pCR Rate in Participants Whose Tumors Express Programmed Cell Death Ligand 1 (PD-L1) at a Combined Positive Score (CPS) ≥10
3. Event-Free Survival (EFS) in All Participants
4. EFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 3 months (Time of surgery)
2. Up to approximately 3 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 (OS) in All Participants
2. OS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
3. Disease-Free Survival (DFS) in All Participants
4. DFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
5. Pathologic Downstaging (pDS) Rate in All Participants
6. pDS Rate in Participants Whose Tumors Express PD-L1 at a CPS ≥10
7. Percentage of Participants Experiencing an Adverse Event (AE)
8. Percentage of Participants Discontinuing Study Treatment due to an AE
9. Percentage of Participants Experiencing Perioperative Complications
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 6.5 years
2. Up to approximately 6.5 years
3. Up to approximately 5.5 years
4. Up to approximately 5.5 years
5. Up to approximately 3 months (Time of surgery)
6. Up to approximately 3 months (Time of surgery)
7. Up to approximately 6.5 years
8. Up to approximately 1 year
9. Up to approximately 1 year
|
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| 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 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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