Evaluation of Atezolizumab Combined with Radiotherapy in Muscle-Invasive Bladder Cancer Patients for Pathological Complete Response

Trial ID: 2024-514604-14-00
Sponsor: Grupo Espanol De Oncologia Genitourinaria-Socug

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to determine the **efficacy** of atezolizumab when administered concurrently with radiotherapy in patients with muscle-invasive bladder cancer. The efficacy is specifically measured in terms of pathological complete response, defined as a response of grade 5 according to the Miller and Payne criteria, in patients treated with the intent of bladder preservation. This objective is clinically relevant as it aims to assess the potential of atezolizumab to enhance treatment outcomes and preserve bladder function in affected patients.

Secondary objectives include: - Evaluating overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and bladder intact disease-free survival (BIDFS). - Calculating the number of patients with muscle-invasive and non-muscle-invasive local failure (LF). - Determining the rate of distant metastases and the rate of patients with bladder preservation. - Assessing the rate of immediate or late salvage cystectomy. - Evaluating the safety profile and tolerability of the combination of atezolizumab with concurrent radiotherapy. - Determining the predictive role of the expression of PD-1/PD-L1 and CD8 in terms of pCR, OS, and DFS in bladder cancer patients treated with atezolizumab plus radiotherapy. - Investigating the correlation between the levels of IFN-γ, interleukin 6 (IL-6), interleukin 18 (IL-18), or ITAC (CXCL11 or IP-9) and the efficacy parameters (pCR, OS, and DFS) of the treatment with atezolizumab plus radiotherapy.

Participants

The clinical trial involves participants diagnosed with **muscle-invasive bladder cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically-confirmed diagnosis of muscle-invasive urothelial carcinoma of the bladder, specifically in clinical stages T2-4a N0 M0, and are not candidates for radical cystectomy due to medical reasons, personal refusal, or choice. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care but unable to carry out any work activities. Adequate bone marrow, renal, and liver function are necessary, with specific laboratory criteria outlined for inclusion. The sponsor has not provided the total number of participants involved in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** of **atezolizumab** in combination with radiotherapy for patients diagnosed with **muscle-invasive bladder cancer**. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to span from October 2019 to February 2027, with the primary objective being to assess the pathological complete response, defined as a response of grade 5 according to the Miller and Payne criteria, following the treatment regimen.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, performance status, and adequate organ function. Following the screening, participants will receive **atezolizumab** intravenously, with the maximum treatment period set at 16 weeks. Regular follow-up visits will be scheduled to monitor the participants' health status, treatment adherence, and any adverse effects. The end-of-study visit will conclude the trial, where the final assessment of the primary endpoint will be conducted.

The expected length of participant involvement is approximately 16 weeks, corresponding to the maximum treatment period. However, conditions such as significant adverse reactions, withdrawal of consent, or non-compliance with the study protocol may lead to early termination from the study. Participants are required to adhere to specific contraceptive measures during the study and for a defined period after the last dose of the study medication to prevent pregnancy-related complications. The trial's rigorous design and comprehensive monitoring aim to ensure the collection of reliable data on the therapeutic potential of **atezolizumab** in this patient population.

Treatment

The clinical trial involves the administration of **atezolizumab**, marketed under the name Tecentriq, as the experimental medication. Tecentriq is provided as a 1,200 mg **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and the medication is administered via the **intravenous** route. The dosing schedule involves a maximum daily dose of 1,200 mg, with a total maximum dose of 7,200 mg over the course of the treatment. The maximum treatment period is 16 weeks. Atezolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF05. The active substance is derived from a protein of other origin, and it is not a pediatric formulation. The medication is manufactured by Roche Registration GmbH.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial's primary objective is to evaluate the efficacy of atezolizumab when used concurrently with radiotherapy in patients with muscle-invasive bladder cancer. The study aims to assess the pathological complete response, defined as a response of grade 5 according to the Miller and Payne criteria, in patients treated with the intent of bladder preservation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

The efficacy of **atezolizumab** concurrent with radiotherapy in patients with muscle-invasive bladder cancer will be assessed through the primary endpoint of pathological complete response. This response is defined as a grade 5 response according to the Miller and Payne criteria, evaluated after the end of the treatment. The study aims to determine the effectiveness of the treatment in achieving bladder preservation in patients who are not candidates for radical cystectomy due to medical reasons, refusal, or personal choice. The trial will involve patients with histologically confirmed muscle-invasive urothelial carcinoma of the bladder, specifically in clinical stages T2-4a N0 M0. The assessment of efficacy will be conducted at the conclusion of the treatment period, which is set to last a maximum of 16 weeks. The trial is categorized as a Phase 2 clinical trial, with the primary objective of evaluating the treatment's efficacy in achieving the desired pathological response.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients must be 18 years of age or older.
Patients have histologically-confirmed diagnosis of muscle-invasive urothelial carcinoma of the bladder, in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice.
Patients who refuse treatment with cisplatin-based chemotherapy or in whom treatment with cisplatin-based therapy is not appropriate.
Patients must have ECOG performance status 0 to 2.
Patients must have adequate bone marrow function as defined by absolute neutrophil count >1.500/mm3; platelets >100.000/mm3 and HB ≥ 9g/dl.
Patients must have adequate renal and liver function as defined by calculated creatinine clearance >15ml/min.
Total bilirubin, SGOT (AST) and/or SGPT (ALT) < 2,5 times the upper limit of normal.
International Normalized Ration (INR) or Prothrombin Time (PT): ≤1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
Female participant of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registering the patient. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female participants of childbearing potential should be willing to use two methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
A paraffin-embedded tumour sample must be available for the associate molecular study.

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Exclusion Criteria

Previous treatment with radiotherapy to the bladder, systemic chemotherapy or immune checkpoint inhibitors. Prior intravesical BCG treatment for non-muscle invasive bladder cancer is allowed.
Presence of regional lymph node or metastatic extension of the disease.
Concurrent treatment with other experimental drugs (within 30 days prior to study entry) or other anti-cancer therapy.
History of prior malignancies within the preceding 5 years other than previously treated basal cell carcinoma of the skin, non-muscle invasive bladder cancer, incidental prostate carcinoma Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5) and carcinoma in situ of the cervix.
Evidence of tumour-related moderate/severe hydronephrosis unless stented or with nephrostomy to preserve renal function.
Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy.
Bulky T3/T4a tumours unsuitable for curative treatment (i.e. > 5 cm in any dimension). Tumours measures must be done post-TUR via CT scan.
Patients with serious uncontrolled infection.
Has a known history of active BT (Bacillus Tuberculosis).
Has known history of, or any evidence of active, non-infectious pneumonitis.
Autoimmune diseases other than vitiligo, type I diabetes mellitus, residual hypothyroidism requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid antibody (HCV-Ab) indicating acute or chronic infection.
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
Subjects with a condition requiring systemic treatment with either corticosteroids (equivalent to > 10 mg/day prednisone) or other immune-suppressive medications within 14 days of study drug administration.
Women of child-bearing potential unwilling to be abstinent or use effective methods of birth control.
General medical or psychological conditions that would preclude appropriate informed consent or compliance with the protocol.