| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Urothelial Carcinoma and Muscle Invasive Bladder Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Urothelial Carcinoma and Muscle Invasive Bladder Cancer |
|
| 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 | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 enfortumab vedotin [EV] + pembrolizumab and radical cystectomy [RC] + pelvic lymph node dissection [PLND]) versus Arm B (neoadjuvant gemcitabine + cisplatin and RC + PLND).
2. To compare event-free survival (EFS) in Arm A (perioperative EV + pembrolizumab and RC + PLND) versus Arm B (neoadjuvant gemcitabine + cisplatin and RC + PLND).
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare overall survival (OS) in Arm A (perioperative EV+pembrolizumab & RC + PLND) versus Arm B (neoadjuvant gemcitabine + cisplatin & RC + PLND).
2. 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.
3. To compare rate of pathologic downstaging (pDS) in Arm A (preoperative EV+pembrolizumab & RC + PLND) & Arm B (neoadjuvant gemcitabine + cisplatin & RC + PLND.
4. To evaluate safety & tolerability of perioperative EV+pembrolizumab + RC + PLND in Arm A.
5. To evaluate changes from baseline in health-related quality of life (HRQoL) & time to deterioration, using 2 general instruments (European Organization for Research & Treatment of Cancer [EORTC] QoL questionnaire-Core 30 [QLQ-C30], & European Quality of Life [EuroQoL]- 5 Dimensions, 5-level Questionnaire [EQ-5D-5L]), & 1 disease-specific instrument (Bladder Cancer Index [BCI]). |
|
| 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 |
Exploratory Biomarker Research
Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of pembrolizumab+ EV |
|
| E.3 | Principal 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 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:
- Enfortumab Vedotin: 180 days
- Gemcitabine/Cisplatin: 180 days
- Pembrolizumab: 120 days
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours (serum) or 24 hours (urine) 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.
8. Provides documented informed consent/assent for the study (either the participant or a legally acceptable representative, if applicable).
9. Has an ECOG performance status of 0 or 1.
10. Has adequate organ function as defined in the study protocol. (All screening labs must be collected within 14 days prior to randomization.)
|
|
| E.4 | Principal 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 ADC’s 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.
20. Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection.
21. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
22. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
23. 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.
24. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
25. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through the time periods stated in Inclusion Criteria #6 and #7.
26. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Pathologic Complete Response (pCR) Rate
2. Event-Free Survival (EFS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 34 months
2. Up to approximately 58 months
|
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
2. Disease Free Survival (DFS)
3. Pathologic Downstaging (pDS) Rate
4. Number of Participants Who Experienced An Adverse Event (AE) (Arm A only)
5. Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only)
6. 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
7. Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale
8. Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI)
9. Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ- 5D-5L) Visual Analogue Score (VAS)
10. Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30)
11. TTD in the Physical Functioning Scale per EORTC QLQ-C30
12. TTD in the Urinary, Bowel and Sexual Domains per BCI
13. TTD in the EQ-5D-5L VAS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 58 months
2. From approximately 12 months to up to approximately 58 months
3. Up to approximately 34 months
4. Up to approximately 58 months
5. Up to approximately 37 weeks
6. Baseline, Up to approximately 58 months
7. Baseline, Up to approximately 58 months
8. Baseline, Up to approximately 58 months
9. Baseline, Up to approximately 58 months
10. Up to approximately 58 months
11. Up to approximately 58 months
12. Up to approximately 58 months
13. Up to approximately 58 months |
|
| 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 | 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Singapore |
| South Africa |
| United States |
| France |
| Poland |
| Bulgaria |
| Romania |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Portugal |
| Russian Federation |
| Ukraine |
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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