Avelumab Plus Bacille Calmette-Guerin (BCG) in Patients With Non-muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of avelumab and Bacille Calmette-Guerin (BCG) and see what effects (good and bad) that this combination treatment has on subjects with recurrent bladder cancer.

Detailed Description
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There will be exams, tests and procedures to see if the patient is eligible for the study. Some are part of regular cancer care and others are part of the study. Subjects will also need to complete a research questionnaire at certain points in the study. Subjects will receive treatment of avelumab and intravesical BCG until unacceptable toxicity or tumor progression. Study participation is up to three years.

Official Title
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Phase Ib Study of Avelumab Plus Bacille Calmette-Guerin (BCG) in Patients With Non-muscle Invasive Bladder Cancer (ABC Trial)

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Avelumab
* Biological: BCG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented Non-muscle Invasive Bladder Cancer (NMIBC) Patient with BCG-treated but unresponsive NMIBC (persistent or recurrent defined as tumor lesion present after prior response). Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2. Patients who are able to understand and sign the informed consent form. Age ≥ 18 years old Ability to comply with protocol Life expectancy >/=12 weeks Adequate hematologic and end-organ function per protocol For women of childbearing potential: Negative serum or urine pregnancy test at screening. For both male and female subjects: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after the last dose of study drug. Exclusion Criteria: Evidence of locally advanced or metastatic bladder cancer (including current disease involving renal pelvis, ureter, or prostatic urethra). Evidence of muscle-invasive bladder cancer Evidence of extravesical bladder cancer Active central nervous system (CNS) metastases. Prior treatment with PD-L1 or PD-1 inhibitor. Prior radiation to bladder Known additional malignancy that required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin. Patient is considered a poor medical risk that would interfere with cooperation with the requirements of the study. Patient has a condition or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment. Patient has not recovered (i.e, to ≤Grade 1 or to baseline) from previous intravesical BCG or other anti-cancer therapy induced AEs. Treatment with any approved anti-cancer therapy, including chemotherapy (systemic or intravesical), radiation therapy, or hormonal therapy within 3 weeks prior to the first dose of study treatment Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 4 weeks prior to the first dose of study treatment Pregnant or lactating, or intending to become pregnant during the study a. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to the first dose of study treatment. 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 Allergy or hypersensitivity to components of the avelumab formulation History of autoimmune disease defined per protocol Prior allogeneic stem cell or solid organ transplantation Current use of immunosuppressive medication defined per protocol History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Positive test for HIV Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening); a. Patients with past or resolved hepatitis B (HBV) infection (positive anti-hepatitis B core antigen [anti-HBc] antibody test) are eligible. HBV DNA must be obtained in these patients prior to the first dose of study treatment. Active hepatitis C a. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction assay is negative for HCV RNA. Active infection requiring systemic therapy Severe infections within 4 weeks prior to the first dose of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia Significant cardiovascular disease, such as cerebral vascular accident/stroke (< 6 months prior to enrollment), New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina Administration of a live/attenuated vaccine within 4 weeks prior to the first dose of study treatment, within 5 months following the administration of the last dose of study drug, or anticipation that such a live/attenuated vaccine will be required during the study Other severe acute or chronic medical conditions defined per protocol

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG + Avelumab<br>Combination of avelumab and intravesical BCG. One cycle = 12 weeks (84 days). A standard maintenance therapy regimen will be provided with BCG occurring at Month 3, 6, and 12. Avelumab treatment ends at the conclusion of Month 12 maintenance therapy. | Drug: Avelumab<br>* Induction phase: once weekly for weeks 1-6, once every 2 weeks at week 8, 10, and 12 Maintenance phase: Once every week for weeks 1-3 Once every 2 weeks starting at week 5, until the next BCG treatment<br>Biological: BCG<br>* Induction phase (cycle 1): • Once weekly for weeks 1-6 Maintenance phase (Month 3, 6, and 12): • Once weekly for 3 weeks<br>* Other names: Bacille Calmette-Guérin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Receiving Complete Induction Course | Proportion of patients receiving complete induction course, defined as freedom from DLT preventing completion of at least 5 of 6 treatments of BCG + avelumab | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Receiving Complete Induction Course | completion of at least 2 of 3 treatments within each 5 week period | 5 weeks | 
| Percent of Patients With Complete Response | based on negative cystoscopy and urine cytology. A negative biopsy at 6 months will provide evidence of complete response. | 3 months | 
| Proportion of Patients With Complete Response | based on negative cystoscopy and urine cytology. A negative biopsy at 6 months will provide evidence of complete response. | 6 months | 
| Percent of Patients With Recurrence Free Survival | defined as percent of patients who are alive and free of persistent or recurrent NMIBC based on cystoscopy, cytology and/or biopsy. | 6 months | 
| Proportion of Patients With Recurrence Free Survival | defined as proportion of patients who are alive and free of persistent or recurrent NMIBC based on cystoscopy, cytology and/or biopsy | 12 months | 
| Proportion of Patients With Progression-free Survival | defined by time from day of first treatment to first progression to higher grade or stage, including muscle-invasive disease or death from any cause | 6 months | 
| Proportion of Patients With Progression-free Survival | defined by time from day of first treatment to first progression to higher grade or stage, including muscle-invasive disease or death from any cause | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intravesical BCG, Bacille Calmette-Guerin, avelumab