Avelumab and Bacille Calmette-Guerin for the Treatment of Recurrent Non-muscle Invasive Bladder Cancer, ABC Study

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)
• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2
• Patients who are able to understand and sign the informed consent form
• Ability to comply with protocol
• Life expectancy >= 12 weeks
• Absolute neutrophil count (ANC) >= 1500/uL (without granulocyte colony-stimulating factor support within 2 weeks prior to the first dose of study treatment)
• Platelet count >= 100,000/uL (without transfusion within 2 weeks prior to the first dose of study treatment)
• Hemoglobin >= 9.0 g/dL; patients may be transfused or receive erythropoietic treatment, at least 7 days prior to the first dose of study treatment, to meet this criterion
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Serum bilirubin =< 1.5 x ULN; patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN; this applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
• Creatinine clearance >= 30 milliliters per minute (mL/min) (calculated using the Cockcroft-Gault formula)
• 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 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 inhibitor
• Prior radiation to bladder
• Patient has a 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 adverse events (AEs) * Alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator’s judgment are acceptable
• 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 * Use of hormone-replacement therapy and oral contraceptives is permitted
• 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 * 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, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis * Patients with medically controlled endocrinopathy (e.g., hypothyroidism, adrenal insufficiency), diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
• Prior allogeneic stem cell or solid organ transplantation
• Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• 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 * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Positive test for human immunodeficiency virus (HIV)
• Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening); * Patients with past or resolved hepatitis B (HBV) infection (positive anti-hepatitis B core antigen [anti-HBc] antibody test) are eligible. HBV deoxyribonucleic acid (DNA) must be obtained in these patients prior to the first dose of study treatment
• Active hepatitis C * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction assay is negative for HCV ribonucleic acid (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 including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study