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)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 712
- 试验地点
- 197
- 主要终点
- 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)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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.
研究组 & 干预措施
Durvalumab + Tremelimumab + Enfortumab Vedotin
Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.
干预措施: Enfortumab Vedotin (Drug)
Durvalumab + Tremelimumab + Enfortumab Vedotin
Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.
干预措施: Tremelimumab (Drug)
Durvalumab + Tremelimumab + Enfortumab Vedotin
Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.
干预措施: Durvalumab (Drug)
Durvalumab + Tremelimumab + Enfortumab Vedotin
Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.
干预措施: Radical Cystectomy (Procedure)
Durvalumab + 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.
干预措施: Radical Cystectomy (Procedure)
Cystectomy with or without approved Adjuvant Therapy.
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.
干预措施: Radical Cystectomy (Procedure)
Durvalumab + 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.
干预措施: Enfortumab Vedotin (Drug)
Durvalumab + 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.
干预措施: Durvalumab (Drug)
结局指标
主要结局
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)
时间窗: Up to 84 months
To assess the safety and tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: Up to 84 months
Clinical chemistry will be assessed by thyroid function assessment in units per mL.
Changes in WHO/ECOG performance status (Safety Run-In part)
时间窗: 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 assessed by vital signs (pulse rate) in beats per minute (Safety Run-In part)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- 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.)
- 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)
- 4. Overall survival (Safety Run-in and Main Study part)(Up to 5 years)
- 5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part)(Up to 24 months)
- 6. Overall survival rate at 5 years (Safety Run-in and Main Study part)(At 5 years)
- 7. Disease-free survival (DFS) (Safety Run-in and Main Study part)(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)(3 years)
- 9. Disease-specific survival (DSS) (Safety Run-in and Main Study part)(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)(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)
- 1. To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate (Safety Run-in part)(3 years)
- 2. To evaluate the efficacy of durvalumab + tremelimumab + EV on EFS (Safety Run-in part)(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)
- 4. Overall survival (Safety Run-in and Main Study part)(Up to 5 years)
- 5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part)(Up to 24 months)
- 6. Overall survival rate at 5 years (Safety Run-in and Main Study part)(At 5 years)
- 7. Disease-free survival (DFS) (Safety Run-in and Main Study part)(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)(3 years)
- 9. Disease-specific survival (DSS) (Safety Run-in and Main Study part)(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)(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.)