Muscle Invasive Bladder Cancer
Conditions
Keywords
Bladder Cancer, Immunotherapy, PD-L1, Durvalumab (MEDI4736), Tremelimumab, Enfortumab Vedotin (PADCEV)
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 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.
Detailed description
Not provided
Interventions
DRUGDurvalumab
Anti- PD-L1 Antibody
DRUGTremelimumab
Human IgG2 mAb
DRUGEnfortumab Vedotin
Nectin-4-directed antibody and microtubule inhibitor conjugate
PROCEDURERadical Cystectomy
For cisplatin-ineligible or cisplatin-refusal patients
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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 with T1 stage are allowed only with N1 disease) * 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, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the safety and tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part) | At completion of study treatment by the last patient and at 3 months. | Frequency of Adverse Events. |
| 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) | 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) | 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) | 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) | 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) | Up to 84 months | Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL) |
| 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) | Up to 84 months | Clinical chemistry will be assessed by kidney function assessment in mg/dL |
| 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) | Up to 84 months | Clinical chemistry will be assessed by thyroid function assessment in units per mL. |
| 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) | Up to 84 months | Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count. |
| 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) | Up to 84 months | — |
| Changes in WHO/ECOG performance status (Safety Run-In part) | Up to 84 months | 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. |
| 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) | Up to 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1. To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate (Safety Run-in part) | 3 years | 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. |
| 2. To evaluate the efficacy of durvalumab + tremelimumab + EV on EFS (Safety Run-in part) | 3 years | 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. |
| 3. Pathologic complete response (pCR) rates at time of cystectomy in Arm1 vs Arm3 and Arm 2 vs Arm 3 (Main Study part) | 3 years | 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. |
| 4. Overall survival (Safety Run-in and Main Study part) | Up to 5 years | 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. |
| 5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part) | Up to 24 months | EFS24 is defined as proportion of participants alive and event-free at 24 months |
| 6. Overall survival rate at 5 years (Safety Run-in and Main Study part) | At 5 years | The proportion of participants alive at 5 years (OS5) is defined as the Kaplan-Meier estimate of OS at 5 years after randomization |
| 7. Disease-free survival (DFS) (Safety Run-in and Main Study part) | Up to first recurrence of disease or death up to 5 years | DFS is defined as time from radical cystectomy to recurrence or death, whichever came first, assessed up to 5 years. |
| 8. Pathologic downstaging (pDS) rate-to < pT2 (Safety Run-in and Main Study part) | 3 years | pDS rate is defined as the rate of downstaging to \< pT2, including pT0, pTis, pTa, pT1, and N0 |
| 9. Disease-specific survival (DSS) (Safety Run-in and Main Study part) | from randomization until death due to bladder cancer up to 5 year. | DSS is defined as time from randomization until death due to bladder cancer, assessed up to 5 years. |
| 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) | 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) | 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) | At 3 months after last dose of durvalumab and tremelimumab | — |
| 13. Metastasis-free survival (MFS) (Safety Run-in and Main Study part) | From randomization until the first recognition of distant metastases or death, up to approximately 48 months. | 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. |
Countries
Argentina, Austria, Brazil, Canada, Chile, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Serbia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Vietnam
Outcome results
None listed