Phase III Randomized Trial of Atezolizumab Plus BCG Versus BCG Alone in High-Risk Non-Muscle Invasive Bladder Cancer Patients

Trial ID: 2024-517621-54-00
Protocol: UC-0160/1717
Sponsor: Unicancer

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to evaluate the efficacy of **atezolizumab** in combination with BCG (Bacillus Calmette-Guerin) compared to BCG alone in patients with high-risk non-muscle invasive bladder cancer (NMIBC), as measured by event-free survival. This is clinically relevant as it aims to determine whether the addition of atezolizumab can improve outcomes in this patient population, potentially offering a more effective treatment strategy for high-risk NMIBC.

Secondary objectives include:

Evaluating the efficacy of atezolizumab in association with BCG versus BCG alone as measured by high-grade recurrence-free survival, progression-free survival, disease-specific survival, and overall survival.
Assessing disease worsening in each treatment arm.
Evaluating the complete response rate and duration of response among patients with carcinoma in situ (CIS) tumors, with or without associated papillary disease, in each arm.
Evaluating the safety and tolerability of atezolizumab in association with BCG versus BCG alone.
Assessing quality of life as measured by the EORTC QLQ-C30.
Identifying predictive and prognostic biomarkers of recurrence and bladder cancer detection in tumor tissue, blood, and urine.

Participants

The clinical trial involves participants diagnosed with **high-risk non-muscle invasive bladder cancer (NMIBC)** following transurethral resection of the bladder (TURBT) and pathological assessment. The study population includes both male and female adults aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include the absence of metastasis in the pelvis, abdomen, or chest, confirmed by imaging, and adequate hematologic and end-organ function. Participants must be willing to comply with the protocol, including treatment, scheduled visits, and follow-up examinations. The trial population is selected based on their medical condition and ability to meet the inclusion criteria, with a focus on ensuring participants have a life expectancy of at least 12 weeks and controlled blood pressure. The study does not provide specific details on lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed as an open-label, randomized, phase III study to evaluate the efficacy of **atezolizumab** in combination with Bacillus Calmette-Guerin (BCG) therapy compared to BCG alone in patients with high-risk non-muscle invasive bladder cancer (NMIBC) following transurethral resection of the bladder (TURBT). The primary objective is to assess event-free survival, with secondary endpoints including high-grade recurrence-free survival, progression-free survival, disease-specific survival, overall survival, and quality of life, among others. The trial is expected to run from December 17, 2018, to October 30, 2028, with a maximum treatment period of 12 months for each participant.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as absence of metastasis, adequate hematologic and end-organ function, and an ECOG performance status of ≤ 2. Following successful screening, participants will be randomized to receive either the combination of **atezolizumab** and BCG or BCG alone. Study visits will include regular assessments to monitor treatment efficacy and safety, with follow-up visits scheduled at specific intervals to evaluate primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is anticipated to last up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous methodological standards, ensuring that data collected is robust and reliable. The study's design and procedures are structured to provide comprehensive insights into the therapeutic potential of **atezolizumab** in this patient population, contributing valuable information to the field of oncology.

Treatment

The clinical trial involves the administration of **atezolizumab**, marketed under the name Tecentriq, which is a **humanized immunoglobulin monoclonal antibody**. Tecentriq is provided as a **concentrate for solution for infusion** and is intended for intravenous administration. The pharmaceutical form is a solution for infusion, and the maximum daily dose is 1200 mg, with a total maximum dose of 20400 mg over the treatment period. The treatment duration is set for a maximum of 12 months. Atezolizumab is classified under the ATC code L01FF05 and is produced by Roche Registration GmbH. The active substance, atezolizumab, is derived from a protein of other origin, specifically designed to target and modulate the immune response in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

In addition to the experimental treatment with atezolizumab, the study includes a standard-of-care therapy involving Bacillus Calmette-Guérin (BCG) bladder instillation. BCG is a well-established treatment for high-risk NMIBC and serves as a comparator in this trial. The objective is to evaluate the efficacy of atezolizumab in combination with BCG compared to BCG alone, with the primary endpoint being event-free survival. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

The efficacy of the clinical trial evaluating **Atezolizumab** in combination with BCG for high-risk non-muscle invasive bladder cancer (NMIBC) will be assessed using several primary and secondary endpoints. The primary endpoint is event-free survival, defined as the time from randomization to the first event of interest. Secondary endpoints include high-grade recurrence-free survival, progression-free survival, disease-specific survival, overall survival, and disease worsening. Additionally, complete response will be evaluated at specific timepoints: Week 12, Week 51, and two years post-randomization, defined by normal cystoscopy and cytology results.

Secondary endpoints also encompass the duration of response, frequency and severity of adverse events graded according to NCI CTCAE v5.0, and quality of life assessments using the EORTC QLQ-C30. Quality of life will be measured at baseline and every 12 weeks for the first two years, then every 24 weeks for years three to five. The status of tumor immune-related biomarkers and exploratory biomarkers in various biological samples will be analyzed to assess their association with treatment outcomes. These efficacy parameters will be collected and analyzed at predetermined intervals throughout the trial to ensure comprehensive evaluation of the treatment's impact on patient outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent form after the last endoscopic surgery
Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 7 days prior to the first study treatment
Patients affiliated to the social security system
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
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
Adult men and women ( age ≥ 18 years)
Any high risk non muscle invasive urothelial carcinoma histologically confirmed (mixed histology tumors allowed if urothelial carcinoma histology is predominant) defined on the TURBT
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)
At least one additional (second) resection of the primary tumor has been performed
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
ECOG performance status of ≤ 2
Life expectancy ≥ 12 weeks
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)

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Exclusion Criteria

Patient having received previous BCG therapy for bladder cancer. In addition, for Belgium, patients who have received prior radiation therapy will not be eligible.
Known HIV infection
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.
Known active tuberculosis
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.
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.
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.
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
Prior allogeneic stem cell or solid organ transplant
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
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
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
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
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
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
Serum albumin < 2.5 g/dL
For France and Belgium, person deprived of their liberty or under protective custody or guardianship
For France, patients who have previously experienced a pericardial disorder on prior treatment with other immune-stimulatory anticancer agents.
For Belgium: Any contra-indications for the adjuvant intravesical BCG treatment
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
Malignancies other than UC within 5 years prior to Day 1 of cycle 1 of treatment apart certain exceptions
Pregnancy or breastfeeding
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
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.