A Study to Evaluate Effects of Atezolizumab (anti-PD-L1 antibody) as an Adjuvant Therapy in Patients with High-Risk Muscle-invasive Bladder Cancer who are circulating tumor DNA (ctDNA) positive following cystectomy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Mar 2021 → ongoing

Decision date (initial)

2024-02-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2022-502705-15-00

EudraCT number

2020-004418-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Diagnosis, Safety, Efficacy, Pharmacogenomic, Pharmacogenetic

To evaluate the efficacy of atezolizumab compared with placebo on the basis of investigator-assessed disease-free survival (DFS) in patients who are circulating-tumor DNA (ctDNA)-positive within 24 weeks of cystectomy (primary analysis population)

Secondary objectives 4

1. To evaluate the efficacy of atezolizumab compared with placebo on the basis of overall survival (OS), In all patients who are randomized to receive study treatment regardless the length of time between cystectomy and ctDNA-positive status Independent Review Facility (IRF)-assessed DFS, disease-specific survival (DSS), distant metastasis-free survival (DMFS), health-related quality of life (HRQoL) and ctDNA clearance
2. To evaluate the safety of atezolizumab compared with placebo
3. To characterize the pharmacokinetic (PK) profile of atezolizumab
4. To evaluate the immune response to atezolizumab

Conditions and MedDRA coding

High-risk muscle-invasive bladder cancer

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Histologically confirmed muscle-invasive urothelial carcinoma (MIUC) (also termed transitional cell carcinoma [TCC]) of the bladder. Patients with carcinomas showing mixed histologys are required to have a dominant transitional cell pattern
2. 2. TNM classification (based on American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 8th Edition) at pathological examination of surgical resection. – Patients who received, or did not receive, platinum-based NAC with tumor stage of (y)pT2-4aN0M0 or (y)pT0-4aN+ M0. Patients who have received at least three cycles of a platinum containing regimen will be considered as having received prior NAC Patients who have not received platinum-based NAC must be ineligible ("unfit") for cisplatin-based adjuvant chemotherapy, have refused it, or will not receive it based on the treating physician’s decision. Cisplatin ineligibility is defined by any one of the following criteria: – Impaired renal function (glomerular filtration rate [GFR] < 60 mL/min); GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft‑Gault formula) – A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies – Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or paresthesia including tingling) – ECOG Performance Status of 2
3. 3. Surgical resection of MIUC of the bladder
4. 4. Availability of a surgical tumor specimen that is suitable (adequate quality and quantity) for use in determining PD L1 expression, WES evaluable (ctDNA assay designability) report, and for exploratory biomarker research assessed by central laboratory testing.
5. 5. Submission of a post-surgery matched blood sample for the identification of somatic mutations in tumor tissue
6. 6. Submission of blood sample for plasma ctDNA testing, collected at least 6 weeks post-surgery

Exclusion criteria 6

1. 1. Known PD-L1 IHC result for adjuvant therapy. The decision for the adjuvant therapy should not be based on the PD-L1 IHC result. If a cap is in effect limiting enrollment of PD-L1 negative patients, this exclusion criterion will not apply.
2. 2. Positive test for HIV, with the following exception: -Patients with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load
3. 3. Patients with active hepatitis B virus (HBV) or hepatitis C -Patients with past HBV infection or resolved HBV infection are eligible. A negative HBV DNA test must be obtained in these patients prior to enrollment
4. 4. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
5. 5. Active tuberculosis confirmed by a test performed within 3 months prior to treatment initiation
6. 6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1.Investigator assessed DFS in patients who are ctDNA-positive within 24 weeks of cystectomy (primary analysis population)

Secondary endpoints 14

1. 1. OS in patients who are ctDNA-positive within 24 weeks after cystectomy (primary analysis population)
2. 2. Investigator-assessed DFS in in patients who are ctDNA-positive at any time following cystectomy (all-randomized population)
3. 3. IRF- assessed DFS in the primary analysis population
4. 4. IRF- assessed DFS in all-randomized patients
5. 5. Investigator-assessed DSS in the primary analysis population
6. 6. Investigator-assessed DMFS in the primary analysis population
7. 7. Time to deterioration of function and QoL in the primary analysis population and in the all-randomized population
8. 8. ctDNA clearance in the primary analysis population
9. 9. Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
10. 10. Change from baseline in targeted vital signs
11. 11. Change from baseline in targeted clinical laboratory test results
12. 12. Serum concentration of atezolizumab at specified timepoints
13. 13. Incidence of anti-drug antibodies (ADAs) to atezolizumab during the study
14. 14. Prevalence of ADAs to atezolizumab at baseline

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 7

Locations

9 EU/EEA countries · 60 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 163 files

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

Application history

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