Brief Title: Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients With Muscle Invasive Bladder Cancer Ineligible to Cisplatin

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate (Safety Run-In and Main Study)

Primary Outcome 1 - Timeframe: Up to 3 years

Primary Outcome 2 - Measure: Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on EFS (Safety Run-In and Main Study)

Primary Outcome 2 - Timeframe: Up to 3 years

Primary Outcome 3 - Measure: Safety and Tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)

Primary Outcome 3 - Timeframe: At completion of study treatment by the last patient and at 3 months.

Primary Outcome 4 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by vital signs (blood pressure in mmHg) (Safety Run-In part)

Primary Outcome 4 - Timeframe: Up to 84 months

Primary Outcome 5 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by vital signs (pulse rate) in beats per minute (Safety Run-In part)

Primary Outcome 5 - Timeframe: Up to 84 months

Primary Outcome 6 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by vital signs (respiration rate) in breaths per minute (Safety Run-In part)

Primary Outcome 6 - Timeframe: Up to 84 months

Primary Outcome 7 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by vital signs (temperature) in degrees Celsius (Safety Run-In part)

Primary Outcome 7 - Timeframe: Up to 84 months

Primary Outcome 8 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin s assessed by abnormality in clinical chemistry by liver function (Safety Run-In part)

Primary Outcome 8 - Timeframe: Up to 84 months

Primary Outcome 9 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by abnormality in clinical chemistry by kidney function (Safety Run-In part)

Primary Outcome 9 - Timeframe: Up to 84 months

Primary Outcome 10 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by abnormality in clinical chemistry by thyroid function (Safety Run-In part)

Primary Outcome 10 - Timeframe: Up to 84 months

Primary Outcome 11 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by abnormality in haematology (Safety Run-In part)

Primary Outcome 11 - Timeframe: Up to 84 months

Primary Outcome 12 - Measure: Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by ECG (pulse rate) (Safety Run-In part)

Primary Outcome 12 - Timeframe: Up to 84 months

Primary Outcome 13 - Measure: Changes in WHO/ECOG performance status (Safety Run-In part)

Primary Outcome 13 - Timeframe: Up to 84 months

CONDITION

• M

ELIGIBILITY

Inclusion Criteria:
* Histologically or cytologically documented muscle-invasive UC of the bladder.

- * Participants with transitional cell and mixed transitional/non-transitional cell histologies;

- * Participants with MIBC clinical tumor (T) stage T2-T4aN0/1M0 or UC of the bladder with clinical state T1N1M0.

- * Participants should also have not received prior systemic chemotherapy or immunotherapy for the treatment of MIBC or bladder UC.

- * Medically fit for cystectomy and able to receive neoadjuvant therapy;

- * Patients who have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC;

- * ECOG performance status of 0,1,2 at enrollment.

- * Availability of tumor sample prior to study entry;

- * Must have a life expectancy of at least 12 weeks at randomization.

- * Cisplatin-ineligible, as defined by any of the following criteria (based on Galsky et al 2011) OR Refuse cisplatin based chemotherapy (must be documented in the medical records)
Exclusion criteria:
* Evidence of lymph node (N2+) or metastatic TCC/UC disease at the time of screening.

- * Active infection

- * Uncontrolled intercurrent illness

- * Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti--PD-1, anti PD-L1, or anti-PD-L2 antibodies.

- * Current or prior use of immunosuppressive medication within 14 days before the first dose of IPs.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

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