Atezolizumab Plus Etoposide and Platinum in Small Cell Bladder Cancer

Exclusion Criteria

• •No prior systemic treatment for small-cell bladder cancer (SCBC)
• •Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. (NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post- treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible). Individual cases will be discussed at investigator discretion.
• •Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
• •Patients who have received prior systemic chemotherapy for urothelial bladder cancer.
• •Prior BCG and intravesical chemotherapy are allowed
• •Any metastatic disease including leptomeningeal disease or brain metastasis on baseline brain imaging
• •Uncontrolled tumor-related pain - Patients requiring pain medication must be on a stable regimen at study entry.
• •Patients requiring pain medication must be on a stable regimen at study entry.
• •Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN
• •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
• •Patients with a history of autoimmune-related hypothyroidism who are on thyroid- replacement hormone are eligible for the study.
• •Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• •Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• •Rash must cover \< 10% of body surface area
• •Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• •No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• •Individual cases can be discussed at investigator discretion. Refer to Appendix H for more details
• •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• •Active tuberculosis
• •Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• •Patients who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• •History of malignancy other than small cell bladder cancer within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
• •Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• •Prior allogeneic stem cell or solid organ transplantation
• •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• •Treatment with a live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of Atezolizumab
• •Current treatment with anti-viral therapy for HBV
• •Treatment with investigational therapy within 28 days prior to initiation of study treatment
• •Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• •Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti- TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment.
• •Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.
• •History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• •Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• •Known allergy or hypersensitivity to any component of Cisplatin, carboplatin or etoposide
• •Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months of atezolizumab after the final dose of study treatment. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
• •Patients who have had radiotherapy to the bladder, or radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities