Immunological Response of Bladder Cancer Patients Under BCG

Study Overview
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Brief Summary
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Bladder cancer (BC) is one of the most common cancers worldwide and the most successful example of vaccine in cancer treatment, representing an efficient model for studying the importance of systemic and local immune mechanisms. Despite being the standard of treatment for the last 40 years, the exact mode of action of immunotherapy with the bacillus Calmette-Guérin (BCG) is still poorly defined. In a mechanistic study, the investigators intend to prospectively investigate immunological signatures, including immune-checkpoints, pre and post-treatment in patients with BC, and correlate the cytokines of the immune by-product and BCG administration pathway to understand the independent contributions of BCG priming (prior exposure to BCG) and crosstalk immunotherapy between tumor profiles and immune response of the patient. The proposed research strategy is justified by the need to identify subsets of patients who better respond to an intervention, or to predict why new immunotherapies and drugs may be successful or failed in clinical trials.

Detailed Description
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Recognizing patient-to-patient variability, key data scarcity, and insight into traditional reductionist therapy, the BCG model offers exceptionally compelling opportunities to understand how immune system behavior in health and disease emerges from local, systemic, genetic, epigenetic, cellular, and environmental modulating factors. The application seeks to change the current clinical practice and research paradigms, by using new theoretical concepts, challenging bladder cancer patients with a highly effective, safe, and affordable immunotherapy, the gold standard in the last 40 years of NMIBC, and in light of new concepts and methodologies brought by the paradigm of immune-checkpoint inhibitors that justified the Nobel Prize in Physiology or Medicine in 2018. The current proposal has the potential to impact the prognosis and identification of those who are unlikely to respond to immune-checkpoint inhibitors, scenarios in which important unanswered questions remain, particularly as this class of agents advances along the spectrum of non-metastatic disease. In a mechanistic approach, patients diagnosed with NMIBC and with the indication for intravesical BCG treatment will be randomized to placebo versus a priming intradermic BCG 14 days before the intravesical treatment and followed up to 180 days. The investigators will define important clinical paradigms: The role of the priming effect on the immune system and better understanding of BCG immunotherapy, with a clear potential for improvement of bladder cancer treatment in NMIBC and MIBC scenarios; The potential of BCG, a widely used vaccine, to improve or impair the results of new immunotherapies, given its long-lasting effect; Rational to develop future treatment associations of BCG and immune-checkpoints. \ Under the new immunological concepts, a better understanding of tumor-associated immune responses in BC patients could provide more informed clinical decisions and treatment optimization. Considering the growing need of assessing the value of treatment at the expense of cost, part of our proposal strategy is to limit financial toxicity as an important issue in cancer treatment and new immunotherapies.

Official Title
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Systemic Immunological Response of Bladder Cancer Patients Under Bacillus Calmette Guérin Treatment

Conditions
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Bladder Cancer, Bacillus Calmette-Guerin

Intervention / Treatment
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* Biological: Bacillus Calmette Guerin
* Other: PLACEBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NMIBC with the indication for intravesical BCG treatment; Exclusion Criteria: Previous BCG treatment; Muscle invasive tumor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BCG intradermal vaccine<br>Intradermal BCG Group (n=16): 0.1 ml of lyophilized, live, and attenuated BCG intradermal vaccine, containing between 2 and 8 x 1.000.000 C.F.U in a single dose. | Biological: Bacillus Calmette Guerin<br>* 0.1 ml of lyophilized, live, and attenuated BCG intradermal vaccine, containing between 2 and 8 x 1.000.000 C.F.U in a single dose.<br>* Other names: BCG;|
| Placebo Comparator: Placebo<br>Placebo group (n = 16): 0.9% saline solution in the same volume as BCG vaccine in a single dose. | Other: PLACEBO<br>* 0.1 ml 0.9% saline in the same volume as the BCG vaccine in a single dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow Cytometry | Cellular Immune Response | Day 0 | 
| Flow Cytometry | Cellular Immune Response | Day 14 | 
| Flow Cytometry | Cellular Immune Response | Day 21 | 
| Flow Cytometry | Cellular Immune Response | Day 35 | 
| Flow Cytometry | Cellular Immune Response | Day 49 | 
| Flow Cytometry | Cellular Immune Response | Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Effects and Change from Baseline Voiding Symptoms | American Urological Association Symptom Score Questionnaire - minimum 0 and maximum 35, higher scores mean a worse outcome. | Day 21 | 
| Adverse Effects and Change from Baseline Voiding Symptoms | American Urological Association Symptom Score Questionnaire - minimum 0 and maximum 35, higher scores mean a worse outcome. | Day 35 | 
| Adverse Effects and Change from Baseline Voiding Symptoms | American Urological Association Symptom Score Questionnaire - minimum 0 and maximum 35, higher scores mean a worse outcome. | Day 49 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG, Bladder cancer, Immunotherapy