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Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients With Muscle Invasive Bladder Cancer Ineligible to Cisplatin (VOLGA)

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ClinicalTrials.gov Identifier: NCT04960709
Recruitment Status : Recruiting
First Posted : July 14, 2021
Last Update Posted : June 6, 2022
Sponsor:
Information provided by (Responsible Party):
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 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 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 830 patients, who will receive triplet combination, duplet combination of Durvalumab and Enfortumab vedotin 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.


Condition or disease Intervention/treatment Phase
Muscle Invasive Bladder Cancer Drug: Durvalumab Drug: Tremelimumab Drug: Enfortumab Vedotin Procedure: Radical Cystectomy Biological: Nivolumab Phase 3

Detailed Description:
Not provided

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 830 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel
Masking: None (Open Label)
Primary Purpose: Treatment
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 Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer
Actual Study Start Date : August 5, 2021
Estimated Primary Completion Date : July 18, 2025
Estimated Study Completion Date : September 8, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Durvalumab + Tremelimumab + 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.
Drug: Durvalumab
Anti- PD-L1 Antibody
Other Names:
  • IMFINZI
  • MEDI4736

Drug: Tremelimumab
Human IgG2 mAb

Drug: Enfortumab Vedotin
Nectin-4-directed antibody and microtubule inhibitor conjugate
Other Name: PADCEV

Procedure: Radical Cystectomy
For cisplatin-ineligible patients

Experimental: 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.
Drug: Durvalumab
Anti- PD-L1 Antibody
Other Names:
  • IMFINZI
  • MEDI4736

Drug: Enfortumab Vedotin
Nectin-4-directed antibody and microtubule inhibitor conjugate
Other Name: PADCEV

Procedure: Radical Cystectomy
For cisplatin-ineligible patients

Active Comparator: 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.
Procedure: Radical Cystectomy
For cisplatin-ineligible patients

Biological: Nivolumab
Adjuvant treatment for MIBC based on pathological high risk criteria (defined as pT3, pT4, or pN+).
Other Name: OPDIVO




Primary Outcome Measures :
  1. Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate (Safety Run-In and Main Study) [ Time Frame: Up to 3 years ]
    Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review using specimens obtained via cystectomy, up to 3 years.

  2. Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on EFS (Safety Run-In and Main Study) [ Time Frame: 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.

  3. Safety and Tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part) [ Time Frame: At completion of study treatment by the last patient and at 3 months. ]
    Frequency of Adverse Events.

  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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) [ Time Frame: Up to 84 months ]
    Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL)

  9. Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in clinical chemistry by kidney function (Safety Run-In part) [ Time Frame: Up to 84 months ]
    Clinical chemistry will be assessed by kidney function assessment in mg/dL

  10. 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) [ Time Frame: Up to 84 months ]
    Clinical chemistry will be assessed by thyroid function assessment in units per mL.

  11. 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) [ Time Frame: Up to 84 months ]
    Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count.

  12. Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by ECG (pulse rate) (Safety Run-In part) [ Time Frame: Up to 84 months ]
  13. Changes in WHO/ECOG performance status (Safety Run-In part) [ Time Frame: 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.


Secondary Outcome Measures :
  1. 1.Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 (Safety Run-In and Main Study) [ Time Frame: 3 years ]
    Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review using specimens obtained via cystectomy, at 3 years.

  2. 2.Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 (Safety Run-In and Main Study) [ Time Frame: Up to 5 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 5 years.

  3. 3.Overall survival (Main Study part) [ Time Frame: 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.

  4. 4.EFS at 24 months (EFS24) (Main Study part) [ Time Frame: Up to 24 months ]
    EFS24 is defined as proportion of participants alive and event-free at 24 months

  5. 5.Overall survival rate at 5 years (Main Study part) [ Time Frame: 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

  6. 6.Disease-free survival (DFS) (Main Study part) [ Time Frame: 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.

  7. 7.Pathologic downstaging (pDS) rate-to < pT2 (Main Study part) [ Time Frame: 3 years ]
    pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0

  8. 8.Disease-specific survival (DSS) (Main Study part) [ Time Frame: 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.

  9. 9.EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) (Main Study part) [ Time Frame: from baseline and time to definitive clinically, assessed up to 5 years ]
  10. 10.Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) (Main Study part) [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]
  11. 11.Area under the Plasma Concentration versus Time Curve (AUCτ) of durvalumab and tremelimumab (Main Study part) [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]
  12. 11.Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Main Study part) [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]
  13. 12. Metastasis-free survival (MFS) (Main Study part) [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04960709


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04960709    
Other Study ID Numbers: D910PC00001
First Posted: July 14, 2021    Key Record Dates
Last Update Posted: June 6, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Bladder Cancer
Immunotherapy
PD-L1
Durvalumab (MEDI4736)
Tremelimumab
Enfortumab Vedotin (PADCEV)
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Nivolumab
Durvalumab
Tremelimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action