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
- Conditions
- Muscle Invasive Bladder Cancer
- Interventions
- Registration Number
- NCT04960709
- Lead Sponsor
- AstraZeneca
- 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 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 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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 712
- 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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Durvalumab + Tremelimumab + Enfortumab vedotin Enfortumab Vedotin 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. Durvalumab + Enfortumab vedotin Enfortumab Vedotin 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. Durvalumab + Enfortumab vedotin Radical Cystectomy 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. Cystectomy with or without approved Adjuvant Therapy. Radical Cystectomy 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. Durvalumab + Tremelimumab + Enfortumab vedotin Radical Cystectomy 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. Durvalumab + Enfortumab vedotin Durvalumab 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. Durvalumab + Tremelimumab + Enfortumab vedotin Durvalumab 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. Durvalumab + Tremelimumab + Enfortumab vedotin Tremelimumab 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.
- Primary Outcome Measures
Name Time Method 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.
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 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 (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)
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 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 (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 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 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 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
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 Outcome Measures
Name Time Method 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 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 pathological review using specimens obtained via cystectomy, at 3 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
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 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.
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.
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.
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.
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
Trial Locations
- Locations (1)
Research Site
🇻🇳Hue, Vietnam