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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Oct 2021 → ongoing

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-507342-84-00

EudraCT number

2020-005452-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy, Pharmacokinetic

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 (Arm 1) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3) on EFS

Secondary objectives 8

1. Safety Run-In (SRI): To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate and Event-free survival (EFS)
2. Main Study: To compare the efficacy of durvalumab + tremelimumab + EV (Arm 1) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3)
3. Main Study: To further compare the efficacy of durvalumab + tremelimumab + EV (Arm 1) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3) on pCT rate, EFS24, OS5, DFS, pDS rate, DSS, and MFS
4. Main Study: To compare the efficacy of durvalumab + tremelimumab + EV (Arm 1) relative to durvalumab + EV (Arm 2) on pCR rate, EFS, OS, EFS24, OS5, DFS, pDS rate, DSS, and MFS
5. Main Study: To assess disease-related symptoms, functioning, and global health status/quality of life in participants treated with durvalumab + tremelimumab + EV (Arm 1) compared with cystectomy (Arm 3), and durvalumab + EV (Arm 2) compared with cystectomy (Arm 3)
6. Main Study: To assess the PK of durvalumab and tremelimumab
7. Main Study: To investigate the immunogenicity of durvalumab and tremelimumab
8. Main Study: To assess the safety and tolerability of durvalumab + tremelimumab + EV (Arm 1) compared with cystectomy (Arm 3), and durvalumab + EV (Arm 2) compared with cystectomy (Arm 3) in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin

Conditions and MedDRA coding

Bladder Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Participants with histologically or cytologically documented muscle-invasive TCC (also known as UC) of the bladder.
2. Participants with transitional cell and mixed transitional / non-transitional cell histologies
3. Participants with MIBC clinical tumor (T) stage T2-T4aN0/1M0 or UC of the bladder with clinical stage T1N1M0 (participants with T1 stage are allowed only with N1 disease) according to the American Joint Committee on Cancer Staging Manual TCC of the bladder
4. Participants should also have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC or bladder UC
5. Medically fit for cystectomy and able to receive neoadjuvant therapy
6. ECOG performance status of 0, 1, 2 at enrollment
7. Availability of tumor sample prior to study entry
8. Cisplatin-ineligible, as defined by any of the following criteria (based on Galsky et al 2011) or Refuse cisplatin based chemotherapy
9. Must have a life expectancy of at least 12 weeks at randomization

Exclusion criteria 5

1. Evidence of lymph node (N2-3) or metastatic TCC/UC disease at the time of screening.
2. Active infection
3. Uncontrolled intercurrent illness
4. 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
5. Current or prior use of immunosuppressive medication within 14 days before the first dose of IPs

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety Run-In (SRI): Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and WHO/ECOG performance status.
2. Main Study: EFS (per BICR or by central pathology review if a biopsy is required for a suspected new lesion) 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

Secondary endpoints 10

1. Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathology and central independent review using specimens obtained via cystectomy.
2. Main Study: EFS (per BICR or by central pathology review if a biopsy is required for a suspected new lesion) 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.
3. Main Study: OS is defined as the length of time from randomization until the date of death due to any cause.
4. Main Study: - pCR rate as defined in the Safety Run-in; - The proportion of participants alive and event-free at 24 months (EFS24; per BICR or by central pathology review if a biopsy is required for a suspected new lesion) is defined as the Kaplan-Meier estimate of EFS at 24 months after randomization • OS5 is defined as the Kaplan-Meier estimate of OS at 5 years after randomization
5. Main Study: DFS (per BICR or by central pathology review if a biopsy is required for a suspected new lesion) defined as the time from the date of radical cystectomy to the first recurrence of disease post radical cystectomy, or death due to any cause, whichever occurs first in MIBC participants who undergo radical cystectomy
6. Main Study: pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0; - DSS is defined as the time from the date of randomization until death due to bladder cancer; - MFS is defined as the time from date of randomization until the first recognition of distant metastases or death, whichever occurs first; - pCR rate as defined above in the SRI; - EFS, OS, EFS24, OS5, DFS, pDS rate, DSS, MFS defined as secondary endpoints above.
7. Adjusted mean change from baseline and time to definitive clinically meaningful deterioration in EORTC QLQ-C30 scale/item scores (prioritized domains: fatigue and pain, physical functioning, and global health status/QoL)
8. Concentration of durvalumab and tremelimumab in serum and PK parameters
9. Presence of ADAs for durvalumab and tremelimumab
10. Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and WHO/ECOG performance status, as described for the corresponding safety run-in objectives and endpoints

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 11

Locations

9 EU/EEA countries · 87 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 70 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications