| 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 or decline 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 event-free survival (EFS) between Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and radical cystectomy plus pelvic lymph node dissection [RC+PLND]) and Arm B (RC+PLND). |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare EFS between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B.
2. To compare OS between Arm C and Arm B and between Arm A and Arm B.
3. To compare pathologic complete response (pCR) rates between Arm C and Arm B and between Arm A and Arm B, based on central pathologic review.
4. To assess disease-free survival (DFS) in participants from Arm A, Arm B, and Arm C who are disease-free after surgery.
5. To compare the rates of pathologic downstaging (pDS) between Arm A and Arm B and between Arm C and Arm B.
6. 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 urothelial carcinoma/MIBC (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology 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. UCs invading into the prostatic stroma with no histologic muscle invasion is allowed, provided that the extent of disease is confirmed via imaging.
-Have clinically nonmetastatic 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 listed below OR be eligible for treatment with cisplatin, but decline treatment with cisplatin-based chemotherapy.
*Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method Modification of Diet of Renal Disease (MDRD) equationsor measured by 24-hour urine collection)
*ECOG Performance Status 2
*CTCAE v.4 Grade ≥2 audiometric hearing loss
*New York Heart Association (NYHA) Class III heart failure
-Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days [+ 14 days] prior to study enrollment [documented informed consent]) that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression assessment.
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 laboratory tests should be performed within 14 days prior to randomization)
-Participant is male or female at least 18 years of age, at the time of providing informed consent
-Male participants are eligible to participate if they agree to the
following during the intervention period and for at least 180 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 180 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 documented informed consent/assent for the study. |
|
| E.4 | Principal exclusion criteria |
-Has a known additional nonurothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization.
-Participants with ≥ N2 disease or metastatic disease (M1) as identified by imaging.
-Has received any prior systemic treatment, chemoradiation, and / or radiation therapy for MIBC or NMIBC.
-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 coinhibitory 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.
-Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are 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 hypersensitivity (≥ Grade 3) to enfortumab vedotin or any 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 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 (noninfectious) 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. Refer to Appendix 6 for country-specific requirements.
- Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority (see Appendix 7). Refer to Appendix 6 for country-specific requirements.
- 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. Refer to Appendix 6 for -country-specific requirements.
- 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 allogeneic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Event-Free Survival (EFS) between Arm C and Arm B |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 7.7 years |
|
| E.5.2 | Secondary end point(s) |
1. EFS between Arm A and Arm B
2. Overall Survival (OS) between Arm C and Arm B
3. Overall Survival (OS) between Arm A and Arm B
4. Pathological Complete Response (pCR) Rate between Arm C and Arm B
5. pCR Rate between Arm A and Arm B
6. Disease-Free Survival (DFS)
7. Pathologic Downstaging (pDS) Rate between Arm A and Arm B
8. pDS Rate between Arm C and Arm B
9. Number of Participants Experiencing an Adverse Event (AE)
10. Number of Participants Discontinuing Study Treatment due to an AE
11. Number of Participants Experiencing Perioperative Complications |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 7.7 years
2. Up to approximately 8.4 years
3. Up to approximately 8.4 years
4. Up to approximately 5.7 years
5. Up to approximately 5.7 years
6. Up to approximately 7.7 years
7. Up to approximately 5.7 years
8. Up to approximately 5.7 years
9. Up to approximately 8.4 years
10. Up to approximately 1 year
11. 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 108 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Colombia |
| India |
| Israel |
| Mexico |
| Thailand |
| United States |
| Viet Nam |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Belgium |
| Croatia |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Spain |
| Sweden |
| Korea, Republic of |
| United Kingdom |
|
| 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
|
| Receipt of the last laboratory test result or LVLS, whichever comes last. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
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