Nivolumab Plus Chemoradiotherapy in Patients With Muscle-invasive Bladder Cancer (MIBC) Not Undergoing Cystectomy

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect synchronous use of nivolumab in addition to chemoradiotherapy in patients withnon-metastatic MIBC who are not candidates for radical cystectomy

Detailed Description
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The initial hypothesis is that addition of nivolumab will increase 2-year locoregional control rate from 55% (control arm) to 75% (immunotherapy arm) There is a 24 month accrual period during which 78 patients will be randomized in a control group (standard chemo-radiotherapy) and the treatment group (chemo-radiotherapy + Nivolumab) The primary objective would be to compare locoregional control rate at 2-years between patients with MIBC receiving or not receiving nivolumab in addition to chemoradiotherapy. The secondary objectives are To study the safety of the addition of nivolumab to chemoradiotherapy in patients with MIBC To compare 2-year bladder cancer failure-free (BCFF) rates, defined as distant metastasis free survival (MFS) AND/OR locoregional failure (defined as in primary objective) To compare median overall survival (OS) in patients with MIBC receiving or not receiving nivolumab in addition to chemoradiotherapy Assess the effect of combined treatment on the quality of life Correlative studies of outcomes with PD-L1expression and with lymphocytic populations in the environment of the tumor

Official Title
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Nivolumab Plus Chemoradiotherapy in Patients With Muscle-invasive Bladder Cancer (MIBC) Not Undergoing Cystectomy: a Phase II, Randomized Study

Conditions
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Bladder Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Other: chemoradiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven, muscle-invasive carcinoma of the bladder, cT2-T4aN0M0 Urothelial, squamous or glandular histology according to WHO 2016 classification (Fig 1) Undergone a vigorous TURB Not candidates for radical cystectomy. PS:0-1 age >18 years old Adequate bone marrow function Adequate renal function Exclusion Criteria: Key Exclusion Criteria Histology other than transitional-cell, squamous or adenocarcinoma Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer cervix or breast. Previous systemic chemotherapy or prior biologic agents within 4 weeks, or intravesical Bacillus Calmette-Guerin (BCG) within 6 weeks of the first dose of study treatment. Prior treatment with any PD-1 or PDL-1 inhibitor or anti CTLA4 agent Previous pelvic radiation therapy. Patients with inherited syndromes associated with hypersensitivity to ionizing radiation Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation Any history of inflammatory bowel disease and or history of abdominal fistula Previous allergy to any of the study drugs

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
Interventional Model Description: randomized controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Chemoradiotherapy<br>standard of care chemo-radiotherapy | Other: chemoradiotherapy<br>* standard of care chemoradiotherapy<br>|
| Experimental: Combination<br>standard of care chemo-radiotherapy + Nivolumab | Biological: Nivolumab<br>* standard of care chemoradiotherapy + Nivolumab<br>Other: chemoradiotherapy<br>* standard of care chemoradiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional control rate | To compare locoregional control rate at 2-years between patients with MIBC receiving or not receiving nivolumab in addition to chemoradiotherapy | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of treatment-related adverse event (safety and tolerability) | Incidence of adverse events as assessed by CTCAE. After radiotherapy completion, AEs will be assessed according to RTOG/EORTC Late Radiation Morbidity Scoring Schema | 2 years | 
| Bladder cancer failure-free (BCFF) rates | To compare 2-year bladder cancer failure-free (BCFF) rates, defined as distant metastasis free survival (MFS) AND/OR locoregional failure (defined as in primary objective) | 2 years | 
| Median overall survival (OS) | To compare median overall survival (OS) in patients with MIBC receiving or not receiving nivolumab in addition to chemoradiotherapy | 2 years | 
| Assessment of the effect of the combined treatment on the quality of life | Quality of life score assessed by Quality of Life of Cancer Patients Questionnaire (EORTC QLQ-C30). Discomfort measured in a scale from 1 (not at all) to 4 (very much) Overall health and quality of life score measured in a scale from 1 (very poor) to 7 (excellent) | 2 years |