History of Changes for Study: NCT04960709

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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Study Record Versions

Version	Submitted Date	Changes
1	July 2, 2021	None (earliest Version on record)
2	August 6, 2021	Study Status, Outcome Measures, Arms and Interventions, Contacts/Locations and Study Design
3	August 24, 2021	Recruitment Status, Study Status, Contacts/Locations and Oversight
4	September 21, 2021	Contacts/Locations and Study Status
5	October 21, 2021	Study Status and Contacts/Locations
6	November 17, 2021	Contacts/Locations and Study Status
7	June 3, 2022	Arms and Interventions, Contacts/Locations, Outcome Measures, Study Status, Eligibility and Study Description
8	July 18, 2022	Arms and Interventions, Contacts/Locations, Study Status, Study Identification, Eligibility, Outcome Measures and Study Description
9	September 1, 2022	Contacts/Locations and Study Status
10	October 10, 2022	Contacts/Locations and Study Status
11	November 8, 2022	Study Status and Contacts/Locations
12	December 9, 2022	Study Status and Contacts/Locations
13	January 24, 2023	Study Status and Contacts/Locations
14	February 17, 2023	Study Status and Contacts/Locations
15	March 21, 2023	Study Status and Contacts/Locations
16	April 27, 2023	Contacts/Locations and Study Status
17	June 13, 2023	Contacts/Locations, Study Status and Study Identification
18	August 4, 2023	Contacts/Locations and Study Status
19	December 12, 2023	Contacts/Locations and Study Status
20	January 24, 2024	Contacts/Locations and Study Status
21	February 23, 2024	Study Status
22	March 21, 2024	Contacts/Locations and Study Status

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	D910PC00001
Brief Title:	Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients With Muscle Invasive Bladder Cancer Ineligible to Cisplatin (VOLGA)
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
Secondary IDs:

Study Status


Record Verification:	July 2021
Overall Status:	Not yet recruiting
Study Start:	August 31, 2021
Primary Completion:	July 31, 2025 [Anticipated]
Study Completion:	September 29, 2028 [Anticipated]

First Submitted:	June 17, 2021
First Submitted that Met QC Criteria:	July 2, 2021
First Posted:	July 14, 2021 [Actual]

Last Update Submitted that Met QC Criteria:	July 2, 2021
Last Update Posted:	July 14, 2021 [Actual]

Sponsor/Collaborators


Sponsor:	AstraZeneca
Responsible Party:	Sponsor
Collaborators:

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description


Brief Summary:	A Global 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
Detailed Description:	Not provided

Conditions


Conditions:	Muscle Invasive Bladder Cancer
Keywords:	Bladder Cancer Immunotherapy PD-L1 Durvalumab (MEDI4736) Tremelimumab Enfortumab Vedotin (PADCEV)

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 3
Interventional Study Model:	Parallel Assignment
	Parallel
Number of Arms:	3
Masking:	None (Open Label)
Allocation:	Randomized
Enrollment:	1080 [Anticipated]

Arms and Interventions

Arms	Assigned Interventions
Experimental: Arm 1 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 1500 mg by intravenous (IV) infusion given on Day 1 of each cycle. Tremelimumab 75 mg by intravenous (IV) infusion given on Cycle 1 Day 1 and Cycle 2 Day 8 preoperatively and on Cycle 1 Day 1 postoperatively. Enfortumab Vedotin 1.25 mg/kg by intravenous (IV) infusion given on Days 1 and 8 of each 21-day cycle	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 Names: PADCEV Procedure: Radical Cystectomy For cisplatin-ineligible patients
Experimental: Arm 2 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 1500 mg by intravenous (IV) infusion given on Day 1 of each cycle. Enfortumab Vedotin 1.25 mg/kg by intravenous (IV) infusion given on Days 1 and 8 of each 21-day cycle.	Drug: Durvalumab Anti- PD-L1 Antibody Other Names: IMFINZI MEDI4736 Drug: Enfortumab Vedotin Nectin-4-directed antibody and microtubule inhibitor conjugate Other Names: PADCEV Procedure: Radical Cystectomy For cisplatin-ineligible patients
Active Comparator: Arm 3 Radical cystectomy alone. Participants receive standard of care surgery alone.	Procedure: Radical Cystectomy For cisplatin-ineligible patients

Outcome Measures


Primary Outcome Measures:
1.	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.
2.	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 ]
3.	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 ]
4.	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 ]
5.	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 ]
6.	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)
7.	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.
8.	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 ]
9.	Changes in WHO/ECOG performance status [ Time Frame: Up to 84 months ]
10.	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.
11.	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.
Secondary Outcome Measures:
1.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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 ]
12.	11.Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab [ Time Frame: At 3 months after last dose of durvalumab and tremelimumab ]

Eligibility


Minimum Age:	18 Years
Maximum Age:	130 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Histologically or cytologically documented muscle-invasive TCC of the bladder with clinical stage T2-T4aN0/1M0 with transitional and mixed transitional cell histology; 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.

Contacts/Locations


Central Contact Person:	AstraZeneca Clinical Study Information Center Telephone: 1-877-240-9479 Email: information.center@astrazeneca.com
Locations:

IPDSharing


Plan to Share IPD:	Yes 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 Information: 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

References


Citations:
Links:
Available IPD/Information: