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 (VOLGA)

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ClinicalTrials.gov Identifier: NCT04960709

Recruitment Status : Recruiting

First Posted : July 14, 2021

Last Update Posted : April 28, 2023

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Sponsor:

Information provided by (Responsible Party):

AstraZeneca

Tracking Information

First Submitted Date ^ICMJE

June 17, 2021

First Posted Date ^ICMJE

July 14, 2021

Last Update Posted Date

April 28, 2023

Actual Study Start Date ^ICMJE

August 5, 2021

Estimated Primary Completion Date

July 18, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

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.
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.
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.
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by vital signs (blood pressure in mmHg) (Safety Run-In part) [ Time Frame: 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 vital signs (pulse rate) in beats per minute (Safety Run-In part) [ Time Frame: 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 vital signs (respiration rate) in breaths per minute (Safety Run-In part) [ Time Frame: 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 vital signs (temperature) in degrees Celsius (Safety Run-In part) [ Time Frame: Up to 84 months ]
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin s 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)
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) [ Time Frame: Up to 84 months ]
Clinical chemistry will be assessed by kidney function assessment in mg/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 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.
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 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.
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by ECG (pulse rate) (Safety Run-In part) [ Time Frame: Up to 84 months ]
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.

Original Primary Outcome Measures ^ICMJE

Safety and Tolerability as evaluated by adverse events occurring throughout the study [ Time Frame: At completion of study treatment by the last patient and at 3 months. ]
Frequency of Adverse Events.
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) [ Time Frame: Up to 84 months ]
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed ssessed by vital signs (pulse rate) in beats per minute [ Time Frame: Up to 84 months ]
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 [ Time Frame: Up to 84 months ]
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 [ Time Frame: Up to 84 months ]
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in clinical chemistry [ Time Frame: Up to 84 months ]
Clinical chemistry will be assessed by liver function (Alanine aminotransferase, Aspartate aminotransferase, albumin, total bilirubin), kidney function (e.g. Urea, Creatinine) and endocrine function(TSH, T3 free,T4 free)
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in haematology [ Time Frame: Up to 84 months ]
Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count.
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by ECG (pulse rate) [ Time Frame: Up to 84 months ]
Changes in WHO/ECOG performance status [ Time Frame: Up to 84 months ]
Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate [ 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.
Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on EFS [ 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.

Change History

Current Secondary Outcome Measures ^ICMJE

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.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.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.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.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.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.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.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.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.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.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 ]
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 ]
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.

Original Secondary Outcome Measures ^ICMJE

1.Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 [ 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.Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 [ 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.Overall survival [ 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.EFS at 24 months (EFS24) [ Time Frame: Up to 24 months ]
EFS24 is defined as proportion of participants alive and event-free at 24 months
5.Overall survival rate at 5 years [ 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.Disease-free survival (DFS) [ 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.Pathologic downstaging (pDS) rate-to < pT2 [ Time Frame: 3 years ]
pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0
8.Disease-specific survival (DSS) [ 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.EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) [ Time Frame: from baseline and time to definitive clinically, assessed up to 5 years ]
10.Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]
11.Area under the Plasma Concentration versus Time Curve (AUCτ) of durvalumab and tremelimumab [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]
11.Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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 ^ICMJE

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)

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 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.

Detailed Description

Not provided

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 3

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel

Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Muscle Invasive Bladder Cancer

Intervention ^ICMJE

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 or cisplatin-refusal patients

Study Arms ^ICMJE

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.
Interventions:
- Drug: Durvalumab
- Drug: Tremelimumab
- Drug: Enfortumab Vedotin
- Procedure: Radical Cystectomy
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.
Interventions:
- Drug: Durvalumab
- Drug: Enfortumab Vedotin
- Procedure: Radical Cystectomy
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.

Intervention: Procedure: Radical Cystectomy

Publications *

Not Provided

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

830

Original Estimated Enrollment ^ICMJE

1080

Estimated Study Completion Date ^ICMJE

September 8, 2028

Estimated Primary Completion Date

July 18, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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.
Cisplatin-ineligible, as defined by any of the 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.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years to 130 Years (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact: AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Listed Location Countries ^ICMJE

Argentina, Austria, Brazil, Canada, Chile, Colombia, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Serbia, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT04960709

Other Study ID Numbers ^ICMJE

D910PC00001

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

IPD Sharing Statement ^ICMJE

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
Supporting Materials:	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