A Phase III study evaluating the efficacy of atezoliumab administration in addition to BCG (Bacillus Calmette-Guerin) for 1 year in patients with high-risk non muscle invasive bladder cancer who never received BCG

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-11-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2024-517621-54-00

EudraCT number

2017-004512-19

ClinicalTrials.gov

NCT03799835

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone in patients with high-risk NMIBC, as measured by event-free survival.

Secondary objectives 10

1. To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by high-grade recurrence free survival,
2. To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by progression free survival,
3. To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by disease-specific survival,
4. To evaluate the efficacy of atezolizumab given in association with BCG versus BCG alone as measured by overall survival,
5. To evaluate disease worsening in each arm,
6. To evaluate complete response rate and duration of response among patients with CIS tumor with or without papillary disease associated, in each arm,
7. To evaluate complete response rate and duration of response among patient with CIS.
8. To evaluate the safety and tolerability of atezolizumab in association with BCG versus BCG alone,
9. To assess quality of life as measured by the EORTC QLQ-C30.
10. To identify predictive and prognostic biomarkers of recurrence and bladder cancer detection in tumor tissue, blood and urine.

Conditions and MedDRA coding

High-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of the bladder (TURBT) and pathological assessment.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed informed consent form after the last endoscopic surgery
2. Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 7 days prior to the first study treatment
3. Patients affiliated to the social security system
4. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab
5. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up
6. Adult men and women ( age ≥ 18 years)
7. Any high risk non muscle invasive urothelial carcinoma histologically confirmed (mixed histology tumors allowed if urothelial carcinoma histology is predominant) defined on the TURBT
8. Tumor tissue available from the surgery for central confirmation of the diagnosis and analysis the expression of PD-L1. In case of a second TURBT performed, as per Belgian guidelines, the tumour tissue from the TURBT procedure that supports the primary diagnosis for study eligibility should be the tumour tissue used for the PD-L1 expression testing (applicable only in Belgium)
9. At least one additional (second) resection of the primary tumor has been performed
10. Absence of metastasis in the pelvis, abdomen, or chest, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan no more than 90 days prior to the first study treatment
11. ECOG performance status of ≤ 2
12. Life expectancy ≥ 12 weeks
13. Systolic blood pressure (BP) <160 mmHg and diastolic BP <95 mmHg, as documented within 7 days prior to the first study treatment (hypertension allowed provided it is controlled)

Exclusion criteria 25

1. Patient having received previous BCG therapy for bladder cancer. In addition, for Belgium, patients who have received prior radiation therapy will not be eligible.
2. Known HIV infection
3. Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C.
4. Known active tuberculosis
5. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
6. Signs or symptoms of urinary infection and/or other signs and symptoms > grade 1 (NCI CTCAE v5.0) within 2 weeks prior to Cycle 1, Day 1. Patients receiving therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 are not eligible. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
7. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months before Cycle 1, Day 1, unstable arrhythmias, or unstable angina.
8. Major surgical procedure other than for diagnosis within 4 weeks prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
9. Prior allogeneic stem cell or solid organ transplant
10. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation if such a live, attenuated vaccine will be required during the study
11. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
12. Any approved anti-cancer therapy, including systemic chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment. Hormone-replacement therapy or oral contraceptives are allowed
13. Prior treatment with CD137 agonists or immune checkpoint−blockade therapies, including anti-CD40, anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
14. Treatment with systemic immunostimulatory agents (including but not limited to interferons, IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
15. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
16. Serum albumin < 2.5 g/dL
17. For France and Belgium, person deprived of their liberty or under protective custody or guardianship
18. For France, patients who have previously experienced a pericardial disorder on prior treatment with other immune-stimulatory anticancer agents.
19. For Belgium: Any contra-indications for the adjuvant intravesical BCG treatment
20. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to day 1 of study treatment
21. Malignancies other than UC within 5 years prior to Day 1 of cycle 1 of treatment apart certain exceptions
22. Pregnancy or breastfeeding
23. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
24. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
25. History of autoimmune disease or history of immunosuppression, or conditions associated with congenital or acquired immune deficiency , including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-free survival defined as the time from randomization to the time of first EFS event.

Secondary endpoints 11

1. High-grade recurrence-free survival is defined by reappearance of high risk disease (high grade, T1 or CIS)
2. Progression-free survival is defined as the time from randomization to the date of progression or death. Progression is defined as increase of stage from Ta to T1 or from CIS to T1; progression to MIBC (T≥ 2) or to lymph node N+ or to distant disease M+
3. Disease-specific survival defined as the time from randomization to the date of death from bladder cancer;
4. Overall Survival, defined as the time from randomization to the date of death from any cause
5. Disease worsening, defined as cystectomy or indicative change in therapy, including systemic chemotherapy or radiation therapy. The date of diagnosis (cystoscopy or CT) leading to cystectomy or chemotherapy/radiotherapy will be considered as the time of disease worsening
6. Complete response will be measured among patients with CIS disease with or without papillary tumor at diagnosis, Week 12, Week 51, and 2 years after randomization. It will be defined by normal cystoscopy and normal cytology.
7. Duration of response (DOR) is defined as the interval from response initiation (when either complete or partial response is first determined) to progression or death, whichever occurs first.
8. Frequency, nature, and severity of adverse events graded according to NCI CTCAE v5.0 and immune-related event (irAE)
9. Quality of life will be measured using EORTC QLQ-C30 assessed at baseline and then every 12 weeks for year 1-2 then every 24 weeks for year 3-5
10. Status of tumor immune-related biomarkers in archival and /or freshly obtained tissues;
11. Status of exploratory biomarkers in urine, plasma, whole blood collected before and during treatment with atezolizumab or at recurrence and association with outcome

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

3 EU/EEA countries · 65 investigational sites

By country

Investigational sites

Results and documents

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

Documents 24 files

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

Application history

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