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

Study Overview
=================
Brief Summary
-----------------
A global phase 3, multicenter, randomized, trial, to Determine the Efficacy and Safety of Durvalumab in combination with Tremelimumab and Enfortumab Vedotin or Durvalumab in combination with Enfortumab vedotin for Perioperative Treatment in Patients Ineligible for Cisplatin or who refuse Cisplantin Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer. The goal of the study is to explore the triplet combination of Durvalumab, Tremelimumab and Enfortumab Vedotin in terms of efficacy and safety compared to the current Standard Of Care (SOC). Volga trial consists of two parts: Safety Run-In and Main Study. In total the study aims to enroll approximately 830 patients, who will receive triplet combination, duplet combination of Durvalumab and Enfortumab vedotin or currently approved SOC in the main trial. In the main part of the trial there is two out of three chances of being on a treatment arm and the treatment is assigned at random by a computer system. In this trial patients in the two treatment arms will receive either 3 cycles of neoadjuvant Durvalumab + Tremelimumab + Enfortumab Vedotin or Durvalumab + Enfortumab vedotin and after surgery both treatment arms will continue with adjuvant Durvalumab.

Detailed Description
-----------------
Not provided

Official Title
-----------------
A Phase III Randomized, Open-Label, Multicenter Study to Determine the Efficacy and Safety of Durvalumab in Combination With Tremelimumab and Enfortumab Vedotin or Durvalumab in Combination With Enfortumab Vedotin for Perioperative Treatment in Patients Ineligible for Cisplatin or Who Refuse Cisplatin Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer (VOLGA)

Conditions
-----------------
Muscle Invasive Bladder Cancer

Intervention / Treatment
-----------------
* Drug: Durvalumab
* Drug: Tremelimumab
* Drug: Enfortumab Vedotin
* Procedure: Radical Cystectomy


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab + Tremelimumab + Enfortumab vedotin<br>Participants will receive 3 preoperative 21-day cycles of Durvalumab + Tremelimumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days. | Drug: Durvalumab<br>* Anti- PD-L1 Antibody<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* Human IgG2 mAb<br>Drug: Enfortumab Vedotin<br>* Nectin-4-directed antibody and microtubule inhibitor conjugate<br>* Other names: PADCEV;Procedure: Radical Cystectomy<br>* For cisplatin-ineligible or cisplatin-refusal patients<br>|
| Experimental: Durvalumab + Enfortumab vedotin<br>Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 9 cycles of Durvalumab. Each postoperative cycle is 28 days. | Drug: Durvalumab<br>* Anti- PD-L1 Antibody<br>* Other names: MEDI4736;Drug: Enfortumab Vedotin<br>* Nectin-4-directed antibody and microtubule inhibitor conjugate<br>* Other names: PADCEV;Procedure: Radical Cystectomy<br>* For cisplatin-ineligible or cisplatin-refusal patients<br>|
| Active Comparator: Cystectomy with or without approved Adjuvant Therapy.<br>Participants may receive SoC (nivolumab approved as adjuvant treatment for MIBC based on high risk criteria) per approved label in the country OR Participants receive standard of care surgery (radical cystectomy) alone. | Procedure: Radical Cystectomy<br>* For cisplatin-ineligible or cisplatin-refusal patients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate (Safety Run-In and Main Study) | Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review using specimens obtained via cystectomy, up to 3 years. | Up to 3 years | 
| Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on EFS (Safety Run-In and Main Study) | Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause, up to 3 years. | Up to 3 years | 
| Safety and Tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part) | Frequency of Adverse Events. | At completion of study treatment by the last patient and at 3 months. | 
| 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) |  | Up to 84 months | 
| 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) |  | Up to 84 months | 
| 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) |  | Up to 84 months | 
| 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) |  | Up to 84 months | 
| 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) | Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL) | Up to 84 months | 
| 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) | Clinical chemistry will be assessed by kidney function assessment in mg/dL | Up to 84 months | 
| 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) | Clinical chemistry will be assessed by thyroid function assessment in units per mL. | Up to 84 months | 
| 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) | Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count. | Up to 84 months | 
| 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) |  | Up to 84 months | 
| Changes in WHO/ECOG performance status (Safety Run-In part) | Eastern Cooperative Oncology Group (ECOG) performance status scale range 0 to 5, where 0 is fully active, able to carry on all pre disease performance without restriction - best outcome and 5 -death - worst outcome. | Up to 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 (Safety Run-In and Main Study) | Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review using specimens obtained via cystectomy, at 3 years. | 3 years | 
| 2.Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 (Safety Run-In and Main Study) | Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause, up to 5 years. | Up to 5 years | 
| 3.Overall survival (Main Study part) | Overall Survival is defined as length of time from randomization until the date of death due to any cause, whichever came first, assessed up to 5 years. | Up to 5 years | 
| 4.EFS at 24 months (EFS24) (Main Study part) | EFS24 is defined as proportion of participants alive and event-free at 24 months | Up to 24 months | 
| 5.Overall survival rate at 5 years (Main Study part) | The proportion of participants alive at 5 years (OS5) is defined as the Kaplan-Meier estimate of OS at 5 years after randomization | At 5 years | 
| 6.Disease-free survival (DFS) (Main Study part) | DFS is defined as time from radical cystectomy to recurrence or death, whichever came first, assessed up to 5 years. | Up to first recurrence of disease or death up to 5 years | 
| 7.Pathologic downstaging (pDS) rate-to < pT2 (Main Study part) | pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0 | 3 years | 
| 8.Disease-specific survival (DSS) (Main Study part) | DSS is defined as time from randomization until death due to bladder cancer, assessed up to 5 years. | from randomization until death due to bladder cancer up to 5 year. | 
| 9.EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) (Main Study part) |  | from baseline and time to definitive clinically, assessed up to 5 years | 
| 10.Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) (Main Study part) |  | At 3 months after last dose of durvalumab and tremelimumab | 
| 11.Area under the Plasma Concentration versus Time Curve (AUCτ) of durvalumab and tremelimumab (Main Study part) |  | At 3 months after last dose of durvalumab and tremelimumab | 
| 11.Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Main Study part) |  | At 3 months after last dose of durvalumab and tremelimumab | 
| 12. Metastasis-free survival (MFS) (Main Study part) | MFS is defined as the time from date of randomization until the first recognition of distant metastases or death, whichever occurs first, up to approximately 48 months. | From randomization until the first recognition of distant metastases or death, up to approximately 48 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bladder Cancer, Immunotherapy, PD-L1, Durvalumab (MEDI4736), Tremelimumab, Enfortumab Vedotin (PADCEV)