Clinical trial NCT04960709: 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
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Muscle Invasive Bladder Cancer
Keywords: Bladder Cancer
Immunotherapy
PD-L1
Durvalumab (MEDI4736)
Tremelimumab
Enfortumab Vedotin (PADCEV)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-07-14
Enrollment: 712
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel
Primary purpose: TREATMENT

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

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 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.

Primary outcomes:
measure: To assess the safety and tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)
timeFrame: At completion of study treatment by the last patient and at 3 months.
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 84 months
measure: Changes in WHO/ECOG performance status (Safety Run-In part)
timeFrame: Up to 84 months
measure: 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)
timeFrame: Up to 3 years
Secondary outcomes:
measure: 1. To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate (Safety Run-in part)
timeFrame: 3 years
measure: 2. To evaluate the efficacy of durvalumab + tremelimumab + EV on EFS (Safety Run-in part)
timeFrame: 3 years
measure: 3. Pathologic complete response (pCR) rates at time of cystectomy in Arm1 vs Arm3 and Arm 2 vs Arm 3 (Main Study part)
timeFrame: 3 years
measure: 4. Overall survival (Safety Run-in and Main Study part)
timeFrame: Up to 5 years
measure: 5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part)
timeFrame: Up to 24 months
measure: 6. Overall survival rate at 5 years (Safety Run-in and Main Study part)
timeFrame: At 5 years
measure: 7. Disease-free survival (DFS) (Safety Run-in and Main Study part)
timeFrame: Up to first recurrence of disease or death up to 5 years
measure: 8. Pathologic downstaging (pDS) rate-to < pT2 (Safety Run-in and Main Study part)
timeFrame: 3 years
measure: 9. Disease-specific survival (DSS) (Safety Run-in and Main Study part)
timeFrame: from randomization until death due to bladder cancer up to 5 year.
measure: 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)
timeFrame: from baseline and time to definitive clinically, assessed up to 5 years
measure: 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)
timeFrame: At 3 months after last dose of durvalumab and tremelimumab
measure: 12. Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Safety Run-in and Main Study part)
timeFrame: At 3 months after last dose of durvalumab and tremelimumab
measure: 13. Metastasis-free survival (MFS) (Safety Run-in and Main Study part)
timeFrame: From randomization until the first recognition of distant metastases or death, up to approximately 48 months.
Other outcomes:
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Study officials:
References: