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

Muscle Invasive Bladder Cancer Clinical Trial

— 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 or Who Refuse Cisplatin Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer (VOLGA)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04960709
• Other study ID #: D910PC00001
• Secondary ID: 2020-005452-38
• Status: Recruiting
• Phase: Phase 3
• Start date: August 5, 2021
• Est. completion date: September 8, 2028

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Not provided

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 830
• Est. completion date: September 8, 2028
• Est. primary completion date: July 18, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Muscle Invasive Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Drug:
• Durvalumab
Anti- PD-L1 Antibody
• Tremelimumab
Human IgG2 mAb
• Enfortumab Vedotin
Nectin-4-directed antibody and microtubule inhibitor conjugate

Procedure:
• Radical Cystectomy
For cisplatin-ineligible or cisplatin-refusal patients

Locations

Country	Name	City	State
Argentina	Research Site	Berazategui
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Caba
Argentina	Research Site	Ciudad Autónoma Buenos Aires
Argentina	Research Site	Ciudad de Buenos Aires
Argentina	Research Site	Pergamino
Argentina	Research Site	Pilar
Argentina	Research Site	Rosario
Austria	Research Site	Graz
Austria	Research Site	Krems
Austria	Research Site	Linz
Austria	Research Site	Salzburg
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wiener Neustadt
Brazil	Research Site	Barretos
Brazil	Research Site	Curitiba
Brazil	Research Site	Fortaleza
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	Santa Maria
Brazil	Research Site	Santo André
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Uberlândia
Canada	Research Site	Abbotsford	British Columbia
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Saskatoon	Saskatchewan
Canada	Research Site	Sherbrooke	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Colombia	Research Site	Barranquilla
Colombia	Research Site	Cali
Colombia	Research Site	Medellin
Colombia	Research Site	Medellín
France	Research Site	Amiens
France	Research Site	Bayonne
France	Research Site	Bordeaux Cedex
France	Research Site	Clermont Ferrand
France	Research Site	Lille
France	Research Site	Lyon
France	Research Site	Marseille
France	Research Site	Marseille CEDEX
France	Research Site	Montpellier
France	Research Site	Nice
France	Research Site	Pierre Benite
France	Research Site	Quint-Fonsegrives
France	Research Site	Rennes
France	Research Site	Saint-Priez En Jarez
France	Research Site	Strasbourg
France	Research Site	Suresnes Cedex
France	Research Site	Vandoeuvre les Nancy
Germany	Research Site	Bielefeld
Germany	Research Site	Bochum
Germany	Research Site	Düsseldorf
Germany	Research Site	Giessen
Germany	Research Site	Halle
Germany	Research Site	Hannover
Germany	Research Site	Hannover
Germany	Research Site	Herne
Germany	Research Site	Köln
Germany	Research Site	Magdeburg
Germany	Research Site	Mainz
Germany	Research Site	Mannheim
Germany	Research Site	Muenchen
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Regensburg
Germany	Research Site	Reutlingen
Germany	Research Site	Ulm
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Heraklion
Greece	Research Site	Maroussi, Athens
Hong Kong	Research Site	Shatin
Israel	Research Site	Hadera
Israel	Research Site	Haifa
Israel	Research Site	Holon
Israel	Research Site	Jerusalem
Israel	Research Site	Jerusalem
Israel	Research Site	Tel Aviv
Italy	Research Site	Aviano
Italy	Research Site	Bari
Italy	Research Site	Firenze
Italy	Research Site	Meldola
Italy	Research Site	Milan
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Pozzuoli
Italy	Research Site	Reggio Emilia
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Terni
Italy	Research Site	Tricase
Italy	Research Site	Verona
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Fukuoka-shi
Japan	Research Site	Hamamatsu-shi
Japan	Research Site	Hirosaki-shi
Japan	Research Site	Ichikawa-shi
Japan	Research Site	Kanazawa-shi
Japan	Research Site	Kashihara-shi
Japan	Research Site	Kita-gun
Japan	Research Site	Kobe-shi
Japan	Research Site	Kumamoto-shi
Japan	Research Site	Matsuyama-shi
Japan	Research Site	Miyazaki-shi
Japan	Research Site	Okayama-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osakasayama-shi
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Toyama-shi
Japan	Research Site	Tsukuba-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Seodaemun-gu
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Mexico	Research Site	Colima
Mexico	Research Site	Monterrey
Mexico	Research Site	Monterrey
Mexico	Research Site	Tlalpan
Netherlands	Research Site	Arnhem
Netherlands	Research Site	Breda
Netherlands	Research Site	Groningen
Netherlands	Research Site	Hilversum
Netherlands	Research Site	Hoofddorp
Netherlands	Research Site	Leiden
Netherlands	Research Site	Utrecht
Poland	Research Site	Gdansk
Poland	Research Site	Nowa Sol
Poland	Research Site	Skórzewo
Poland	Research Site	Warszawa
Portugal	Research Site	Braga
Portugal	Research Site	Coimbra
Portugal	Research Site	Faro
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisbon
Portugal	Research Site	Porto
Portugal	Research Site	Vila Nova de Gaia
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Nizhniy Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Ufa
Serbia	Research Site	Belgrad
Serbia	Research Site	Belgrade
Serbia	Research Site	Nis
Serbia	Research Site	Sremska Kamenica
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	Las Palmas de Gran Canaria
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Pamplona
Spain	Research Site	Santander
Spain	Research Site	Sevilla
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
Thailand	Research Site	Dusit
Thailand	Research Site	Songkhla
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Antalya
Turkey	Research Site	Edirne
Turkey	Research Site	Istanbul
Turkey	Research Site	Istanbul
Turkey	Research Site	Karsiyaka
Turkey	Research Site	Malatya
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Kiev
United Kingdom	Research Site	Blackburn
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	Gillingham
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Sheffield
United States	Research Site	Albany	New York
United States	Research Site	Austin	Texas
United States	Research Site	Boston	Massachusetts
United States	Research Site	Brighton	Michigan
United States	Research Site	Brooklyn	New York
United States	Research Site	Buffalo	New York
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Coeur d'Alene	Idaho
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Columbus	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Detroit	Michigan
United States	Research Site	Fort Myers	Florida
United States	Research Site	Fort Worth	Texas
United States	Research Site	Hershey	Pennsylvania
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Irving	Texas
United States	Research Site	Jackson	Mississippi
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Louisville	Kentucky
United States	Research Site	Maywood	Illinois
United States	Research Site	Memphis	Tennessee
United States	Research Site	New Haven	Connecticut
United States	Research Site	New York	New York
United States	Research Site	Norfolk	Virginia
United States	Research Site	Orange	California
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Saddle Brook	New Jersey
United States	Research Site	Santa Monica	California
United States	Research Site	Scarborough	Maine
United States	Research Site	Spokane	Washington
United States	Research Site	Syracuse	New York
United States	Research Site	Tacoma	Washington
United States	Research Site	Washington	District of Columbia
Vietnam	Research Site	Ha Noi
Vietnam	Research Site	Hanoi
Vietnam	Research Site	Ho Chi Minh
Vietnam	Research Site	Ho Chi Minh city
Vietnam	Research Site	Hue

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Vietnam,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate (Safety Run-In and Main Study)	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.	Up to 3 years
Primary	Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on EFS (Safety Run-In and Main Study)	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.	Up to 3 years
Primary	Safety and Tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)	Frequency of Adverse Events.	At completion of study treatment by the last patient and at 3 months.
Primary	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)		Up to 84 months
Primary	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)		Up to 84 months
Primary	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)		Up to 84 months
Primary	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)		Up to 84 months
Primary	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)	Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL)	Up to 84 months
Primary	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)	Clinical chemistry will be assessed by kidney function assessment in mg/dL	Up to 84 months
Primary	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)	Clinical chemistry will be assessed by thyroid function assessment in units per mL.	Up to 84 months
Primary	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)	Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count.	Up to 84 months
Primary	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)		Up to 84 months
Primary	Changes in WHO/ECOG performance status (Safety Run-In part)	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.	Up to 84 months
Secondary	1.Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 (Safety Run-In and Main Study)	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.	3 years
Secondary	2.Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 (Safety Run-In and Main Study)	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.	Up to 5 years
Secondary	3.Overall survival (Main Study part)	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.	Up to 5 years
Secondary	4.EFS at 24 months (EFS24) (Main Study part)	EFS24 is defined as proportion of participants alive and event-free at 24 months	Up to 24 months
Secondary	5.Overall survival rate at 5 years (Main Study part)	The proportion of participants alive at 5 years (OS5) is defined as the Kaplan-Meier estimate of OS at 5 years after randomization	At 5 years
Secondary	6.Disease-free survival (DFS) (Main Study part)	DFS is defined as time from radical cystectomy to recurrence or death, whichever came first, assessed up to 5 years.	Up to first recurrence of disease or death up to 5 years
Secondary	7.Pathologic downstaging (pDS) rate-to < pT2 (Main Study part)	pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0	3 years
Secondary	8.Disease-specific survival (DSS) (Main Study part)	DSS is defined as time from randomization until death due to bladder cancer, assessed up to 5 years.	from randomization until death due to bladder cancer up to 5 year.
Secondary	9.EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) (Main Study part)		from baseline and time to definitive clinically, assessed up to 5 years
Secondary	10.Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) (Main Study part)		At 3 months after last dose of durvalumab and tremelimumab
Secondary	11.Area under the Plasma Concentration versus Time Curve (AUCt) of durvalumab and tremelimumab (Main Study part)		At 3 months after last dose of durvalumab and tremelimumab
Secondary	11.Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Main Study part)		At 3 months after last dose of durvalumab and tremelimumab
Secondary	12. Metastasis-free survival (MFS) (Main Study part)	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.	From randomization until the first recognition of distant metastases or death, up to approximately 48 months.