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 Cisplatin based chemotherapy 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 or the duplet combination of Durvalumab 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 677 patients, who will receive triplet combination, duplet combination or currently approved SOC in the main study. 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 + Enfortumab Vedotin and 2 cycles of Tremelimumab or Durvalumab + Enfortumab vedotin and after surgery both treatment arms will receive either adjuvant Durvalumab or adjuvant Durvalumab and 1 cycle of Tremelimumab.
Not provided
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
712
Anti- PD-L1 Antibody
Human IgG2 mAb
Nectin-4-directed antibody and microtubule inhibitor conjugate
For cisplatin-ineligible or cisplatin-refusal patients
Research Site
Orange, California, United States
Research Site
Santa Monica, California, United States
Research Site
New Haven, Connecticut, United States
Research Site
Washington D.C., District of Columbia, United States
Research Site
Fort Myers, Florida, United States
Research Site
To assess the safety and tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)
Frequency of Adverse Events.
Time frame: At completion of study treatment by the last patient and at 3 months.
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (blood pressure in mmHg) (Safety Run-In part)
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (pulse rate) in beats per minute (Safety Run-In part)
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (respiration rate) in breaths per minute (Safety Run-In part)
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (temperature) in degrees Celsius (Safety Run-In part)
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as 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)
Time frame: 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
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for 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.
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for 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.
Time frame: Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as as assessed by ECG (pulse rate) (Safety Run-In part)
Time frame: 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.
Time frame: Up to 84 months
Compare efficacy of durvalumab + tremelimumab + EV (Arm 1) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3) on EFS (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.
Time frame: Up to 3 years
1. To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate (Safety Run-in part)
Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathology and central independent review using specimens obtained via cystectomy, at 3 years.
Time frame: 3 years
2. To evaluate the efficacy of durvalumab + tremelimumab + EV on EFS (Safety Run-in part)
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.
Time frame: 3 years
3. Pathologic complete response (pCR) rates at time of cystectomy in Arm1 vs Arm3 and Arm 2 vs Arm 3 (Main Study part)
Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathological review using specimens obtained via cystectomy, at 3 years.
Time frame: 3 years
4. Overall survival (Safety Run-in and 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.
Time frame: Up to 5 years
5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part)
EFS24 is defined as proportion of participants alive and event-free at 24 months
Time frame: Up to 24 months
6. Overall survival rate at 5 years (Safety Run-in and 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
Time frame: At 5 years
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Coeur d'Alene, Idaho, United States
Research Site
Maywood, Illinois, United States
Research Site
Indianapolis, Indiana, United States
Research Site
Iowa City, Iowa, United States
Research Site
Louisville, Kentucky, United States
...and 192 more locations
7. Disease-free survival (DFS) (Safety Run-in and Main Study part)
DFS is defined as time from radical cystectomy to recurrence or death, whichever came first, assessed up to 5 years.
Time frame: Up to first recurrence of disease or death up to 5 years
8. Pathologic downstaging (pDS) rate-to < pT2 (Safety Run-in and Main Study part)
pDS rate is defined as the rate of downstaging to \< pT2, including pT0, pTis, pTa, pT1, and N0
Time frame: 3 years
9. Disease-specific survival (DSS) (Safety Run-in and Main Study part)
DSS is defined as time from randomization until death due to bladder cancer, assessed up to 5 years.
Time frame: from randomization until death due to bladder cancer up to 5 year.
10. EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) (Safety Run-in and Main Study part)
Time frame: from baseline and time to definitive clinically, assessed up to 5 years
11. Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) (Safety Run-in and Main Study part)
Time frame: At 3 months after last dose of durvalumab and tremelimumab
12. Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Safety Run-in and Main Study part)
Time frame: At 3 months after last dose of durvalumab and tremelimumab
13. Metastasis-free survival (MFS) (Safety Run-in and 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.
Time frame: From randomization until the first recognition of distant metastases or death, up to approximately 48 months.