Assessment of Efficacy and Safety of Durvalumab Plus BCG Compared to the Standard Therapy With BCG in Non-muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, multi-center, global, phase III study to determine the efficacy and safety of Durvalumab + BCG combination therapy in the treatment of patients with non-muscle-invasive bladder cancer

Detailed Description
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Patients will be randomized in a 1:1:1 ratio to receive treatment with Durvalumab + BCG combination therapies, or Standard of Care (SoC) therapy.

Official Title
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A Phase III Randomized, Open-Label, Multi-Center, Global Study of Durvalumab and Bacillus Calmette-Guerin (BCG) Administered as Combination Therapy Versus BCG Alone in High-Risk, BCG Naïve Non-Muscle Invasive Bladder Cancer Patients

Conditions
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Non-muscle-invasive Bladder Cancer

Intervention / Treatment
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* Biological: Durvalumab (MEDI4736)
* Biological: Bacillus Calmette-Guerin (BCG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study, patients should fulfill the following criteria: Aged at least 18 years BCG-naïve (patients who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry are eligible) Local histological confirmation (based on pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa. A high risk tumor is defined as one of the following T1 tumor High grade/ G3 tumor CIS Multiple and recurrent and large (with diameter of largest tumor ≥3 cm) tumors (all conditions must be met in this point) Complete resection of all Ta/T1 papillary disease prior to randomization, with the TURBT removing high-risk NMIBC performed not more than 4 months before randomization in the study. Patients with residual CIS after TURBT are eligible No prior radiotherapy for bladder cancer No prior exposure to immune-mediated therapy of cancer including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 antibodies. Patients who have been treated with anticancer vaccines will be excluded Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled: Evidence of muscle-invasive, locally advanced, metastatic, and/or extra vesical bladder cancer (ie, T2, T3, T4, and / or stage IV) Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium Previous investigational product (IP) assignment in the present study Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is acceptable. Chemotherapy for previous instances of NMIBC is acceptable. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician Patients with celiac disease controlled by diet alone History of another primary malignancy except for Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of IP and of low potential risk for recurrence during the study period Adequately treated nonmelanoma skin cancer or lentigo maligna withoutevidence of disease Adequately treated CIS without evidence of disease Prostate cancer (tumor/node/metastasis stage) of stage ≤ T2cN0M0 without biochemical recurrence or progression that in the opinion of the Investigator does not require active intervention Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab plus BCG (induction + maintenance)<br>Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy | Biological: Durvalumab (MEDI4736)<br>* Investigational product<br>Biological: Bacillus Calmette-Guerin (BCG)<br>* Standard of care<br>|
| Experimental: Durvalumab plus BCG (induction only)<br>Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy | Biological: Durvalumab (MEDI4736)<br>* Investigational product<br>Biological: Bacillus Calmette-Guerin (BCG)<br>* Standard of care<br>|
| Active Comparator: BCG treatment (Standard of care therapy)<br>Bacillus Calmette-Guerrin (BCG) standard of care treatment | Biological: Bacillus Calmette-Guerin (BCG)<br>* Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy of Durvalumab + BCG (induction plus maintenance) combination therapy compared to SoC in terms of Disease free survival (DFS) in patients with NMIBC |  | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy of Durvalumab + BCG (induction plus maintenance) therapy compare to SoC in terms of DFS after 24 months of last subject's last dose of IP |  | Up to 4 years | 
| Disease-related symptoms and HRQoL in patients with NMIBC treated with Durvalumab + BCG combination therapies compared to SoC and compared to each other using the EORTC QLQ-C30 questionnaire | EORTC QLQ-C30 measures cancer patients' functioning (HRQoL) and symptoms for all cancer types and consists of functional, symptom and a global measure of health status scales | Up to 4 years | 
| Patient-reported treatment tolerability using specific PRO CTCAE symptoms |  | Up to 4 years | 
| The serum concentration of Durvalumab plus BCG combination therapies |  | Up to 4 years | 
| The immunogenicity of Durvalumab when used in combination with BCG treatment assessed by descriptive summary of presence of ADAs | Serum will be tested for the presence of anti-drug antibodies. | Up to 4 years | 
| The efficacy of Durvalumab + BCG (induction plus maintenance) therapy compare to SoC in terms of OS |  | Up to 7 years | 
| The efficacy of Durvalumab + BCG (induction plus maintenance) combination therapy compared to SoC in terms of time to muscle invasive bladder cancer and/or metastatic disease |  | Up to 7 years | 
| The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of DFS after 24 months of last subject's last dose of IP |  | Up to 4 years | 
| The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of DFS after 24 months of last subject's last dose of IP |  | Up to 4 years | 
| The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of OS |  | Up to 7 years | 
| The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of OS |  | Up to 7 years | 
| The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of time to muscle invasive bladder cancer and/or metastatic disease |  | Up to 7 years | 
| The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of time to muscle invasive bladder cancer and/or metastatic disease |  | Up to 7 years | 
| Disease-related symptoms and HRQoL in patients with NMIBC treated with Durvalumab + BCG combination therapies compared to SoC and compared to each other using the the EORTC QLQ NMIBC24 questionnaire | EORTC QLQ-NMIBC24 assesses disease-specific symptoms of patients with intermediate to high-risk NMIBC. | Up to 4 years | 
| The efficacy of durvalumab + BCG combination therapy compared to SoC in terms of CRR for patients with CIS prior to study entry or at baseline cystoscopy | CRR at 6 months in patients with CIS prior to the study entry or at baseline cystoscopy | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Durvalumab, BCG, MEDI4736, NMIBC, PD-L1, DFS, OS