Clinical Trials Register

Summary
EudraCT Number:	2020-005452-38
Sponsor's Protocol Code Number:	D910PC00001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-07-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-005452-38

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Treatment combination of Durvalumab, Tremelimumab, Enfortumab Vedotin in patients with muscle invasive bladder cancer ineligible to cisplatin or Who Refuse Cisplatin

A.3.2

Name or abbreviated title of the trial where available

Volga

A.4.1

Sponsor's protocol code number

D910PC00001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Clinical Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	1800 Concorde Pike
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	19803
B.5.3.4	Country	United States
B.5.4	Telephone number	+1877240 9479
B.5.6	E-mail	information.center@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	IMFINZI
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	Norway
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Durvalumab
D.3.2	Product code	MEDI4736
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	durvalumab
D.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	IMJUDO
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB SE-151 85 Sodertalje Sweden
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tremelimumab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tremelimumab
D.3.9.1	CAS number	745013-59-6
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Padcev
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma US, Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enfortumab vedotin
D.3.2	Product code	EV
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Enfortumab vedotin
D.3.9.3	Other descriptive name	EV
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Documented muscle-invasive urothelial carcinoma (UC) of the bladder in cisplatin ineligible patients or Who Refuse Cisplatin

E.1.1.1

Medical condition in easily understood language

Cancer in thick muscle in the bladder wall

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10005004
E.1.2	Term	Bladder cancer NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Safety Run-In (SRI):To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin
Main Study: To compare the efficacy of durvalumab + tremelimumab + EV relative to cystectomy on pCR rate and EFS

E.2.2

Secondary objectives of the trial

Safety Run-In (SRI): To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate and EFS
Main Study:To compare the efficacy of durvalumab + EV relative to cystectomy on pCR rate, EFS, OS, EFS24, OS5, DFS, pDS rate, and DSS

E.2.3

Trial contains a sub-study

E.3

Principal 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;
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.

E.4

Principal 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.

E.5 End points

E.5.1

Primary end point(s)

Safety Run-In (SRI):
• Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin.
Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and WHO/ECOG performance status.
Main Study:
• Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate and EFS.
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.
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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Main Study
1) pCR rate defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review.
2) EFS as time from randomization to first occurrence of recurrence of disease post-radical cystectomy, first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death.

E.5.2

Secondary end point(s)

1. Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3
2. Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3
3. Overall survival defined as length of time from randomization until the date of death due to any cause
4. EFS at 24 months (EFS24) defined as proportion of participants alive and event-free at 24 months
5. Overall survival rate at 5 years
6. Disease-free survival (DFS) defined as time from radical cystectomy to recurrence or death
7. Pathologic down staging (pDS) rate-to < pT2
8. Disease-specific survival (DSS) defined as time from randomization until death due to bladder cancer
9. Metastasis-free survival (MFS) defined as the time from the date of
randomization until the first recognition of distant metastases or death,
whichever occurs first.
10. QoL in all arms
11. Immunogenicity of Durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA)
12. Assess the pharmacokinetics (PK) of Durvalumab and Tremelimumab

E.5.2.1

Timepoint(s) of evaluation of this end point

OS:length of time from randomization until death
EFS24:proportion of subjects alive and event-free at 24mons as Kaplan-Meier estimate of EFS at 24mons after randomization OS5:Kaplan-Meier estimate of OS at 5yrs after randomization
DFS:time from date of radical cystectomy to first recurrence of disease post-radical cystectomy, or death pDS:rate of downstaging to<pT2, including pT0,pTis,pTa,pT1,N0. DSS:time from date of randomization until death

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Cystectomy without or with approved adjuvant therapy, if approved as a SOC and available locally.

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Chile

Colombia

Hong Kong

Taiwan

Brazil

Canada

Israel

Japan

Korea, Republic of

Mexico

Serbia

Thailand

United Kingdom

United States

Viet Nam

Austria

France

Germany

Greece

Italy

Netherlands

Poland

Portugal

Spain

Türkiye

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the study is defined as the date of the last visit/contact of the last participant in the study globally.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

450

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

379

F.4.2.2

In the whole clinical trial

830

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After final analysis no study drug will be provided

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-14

P. End of Trial
P.	End of Trial Status	Ongoing

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