Urothelial Carcinoma and Muscle Invasive Bladder Cancer MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has a histologically confirmed diagnosis of urothelial carcinoma (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (=50%) urothelial histology and PD-L1 expression (CPS =10 or CPS <10, for PD-L1 not evaluable refer to inclusion criterion #4) to be confirmed by BICR (central pathology and/or central imaging assessment). • 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 component of neuroendocrine histology are not eligible • Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible. Urothelial carcinomas invading into the prostatic stroma with no histologic muscle invasion are allowed, provided that the extent of disease is confirmed via imaging 2. Has clinically non-metastatic bladder cancer (N=1, M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR. 3. Is deemed eligible for RC + PLND by a urologist and/or oncologist and agrees to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines. 4. Has a TUR of a bladder tumor (obtained within 60 days [+14 days] prior to enrollment [ICF documented]) 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. Is male or female, and at least 18 years of age, at the time of providing documented informed consent. 6. 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: -Enfortumab Vedotin: 180 Days -Gemcitabine/Cisplatin: 95 days -Pembrolizumab: 0 Days (no requirement) • 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) • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed. 7. 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
Exclusion criteria
Exclusion criteria: 1. Has a known additional non-urothelial malignancy that is progressing or has required active anticancer treatment =3 years prior to study randomization. 2. Has received any prior systemic treatment, chemoradiation, and/or radiation therapy treatment for MIBC. 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 (calculated by one of the following methods: Cockcroft-Gault method, MDRD formula or 24-hour urine collection) • ECOG performance status = 2 • CTCAE v.5.0 Grade = 2 peripheral neuropathy • CTCAE v 5.0 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 • NYHA Class III or greater 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 prior systemic anticancer therapy including investigational agents within 3 years prior to randomization. (Participants who have previously received EV or other MMAE-based ADCs are excluded) 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 prior to 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 ongoing sensory or motor neuropathy Grade 2 or higher. 12. 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 active autoimmune disease. Physiologic replacement (10 mg/day prednisone equivalent) doses of corticosteroids are permitted for participants with adrenal insufficiency. 13. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients. 14. Has known severe (=Grade 3) hypersensitivity to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20). 15. Has severe hypersensitivity (=Grade 3) to cisplatin and/or gemcitabine and/or any of their excipients. 16. 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. 17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy is allowed. 18. Has a history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c =8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 19. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To compare event-free survival (EFS) in Arm A (perioperative EV + pembrolizumab and RC + PLND) versus Arm B (neoadjuvant gemcitabine + cisplatin and RC + PLND).;Secondary Objective: 1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative EV+pembrolizumab&RC+PLND) versus Arm B (neoadjuvant gemcitabine+cisplatin and RC+PLND). 2. To compare overall survival (OS) in Arm A (perioperative EV+pembrolizumab & RC+PLND) versus Arm B (neoadjuvant gemcitabine+cisplatin & RC+PLND). 3. To assess disease-free survival (DFS) in Arm A (perioperative EV+pembrolizumab & RC+PLND) & Arm B (neoadjuvant gemcitabine + cisplatin & RC+PLND), participants who are disease free after surgery. 4. To compare rate of pathologic downstaging (pDS) in Arm A (preoperative EV+pembrolizumab & RC+PLND) & Arm B (neoadjuvant gemcitabine + cisplatin & RC+PLND. 5. To evaluate safety & tolerability of perioperative EV+pembrolizumab+RC+PLND in Arm A. 6.To evaluate changes from baseline in health-related quality of life (HRQoL) & time to deterioration, using 2 general instruments (EORTC QoL questionnaire-QLQ-C30, & EuroQoL- EQ-5D-5L), & 1 disease-specific instrument (BCI).;Primary end point(s): 1. Event-Free Survival (EFS);Timepoint(s) of evaluation of this end point: 1. Up to approximately 5,5 years | — |
Secondary
| Measure | Time frame |
|---|---|
| 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) (Arm A only) 6. Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only) 7. Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ- C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score 8. Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale 9. Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI) 10. Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ- 5D-5L) Visual Analogue Score (VAS) 11. Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) 12. TTD in the Physical Functioning Scale per EORTC QLQ-C30 13. TTD in the Urinary, Bowel and Sexual Domains per BCI 14. TTD in the EQ-5D-5L VAS ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 42 months 2. Up to approximately 5.5 years XML File Identifier: DMHPPYi4+FTODUFAkegWeuMnaoc= Page 31/43 3. From approximately 12 months to up to approximately 5 years 4. Up to approximately 42 months 5. Up to approximately 5.5 years 6. Up to approximately 52 weeks within each treatment cycle 7. Baseline, Up to approximately 5.5 years 8. Baseline, Up to approximately 5.5 years 9. Baseline, Up to approximately 5.5 years 10. Baseline, 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 | — |
Countries
Argentina, Australia, Bulgaria, Canada, Colombia, Croatia, Czechia, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Malaysia, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, South Africa, Spain, Ukraine, United Kingdom, United States, Viet Nam
Outcome results
None listed