Atezolizumab With Bevacizumab in Previously Untreated Metastatic/Unresectable Urothelial Cancer

Exclusion Criteria

• •Patients meeting any of the criteria below may not participate in the study:
• •Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
• •* Palliative radiotherapy for bone metastases or soft tissue lesions should be completed \> 7 days prior to baseline imaging
• •* Hormone-replacement therapy or oral contraceptives
• •Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
• •Active or untreated central nervous system (CNS) metastases or leptomeningeal disease as determined by computed tomography (CT) scan or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments.
• •Patients with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
• •* Evaluable or measurable disease outside the CNS
• •* No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
• •* No history of intracranial or spinal cord hemorrhage
• •* No evidence of significant vasogenic edema
• •* No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose allowed
• •* No stereotactic radiation, whole-brain radiation within 4 weeks prior to Cycle 1 Day 1
• •* Patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy within 3 months prior to Cycle 1 Day 1 will be excluded
• •* Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study
• •* Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or surgical resection and ≥ 2 weeks since discontinuation of corticosteroids
• •Leptomeningeal disease
• •Uncontrolled tumor-related pain
• •* Patients requiring pain medication must be on a stable regimen at study entry
• •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• •* Patients with indwelling drainage catheters are allowed.
• •Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. NOTE: Patients with asymptomatic hypercalcemia controlled with medical therapy are eligible.
• •* Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
• •* Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while in the study.
• •Malignancies other than urothelial cancer within 5 years prior to Cycle 1 Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score ≤ 3 + 4, and PSA ≤ 0.5 ng/mL undergoing active surveillance and treatment naive)
• •Pregnant or breastfeeding
• •History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• •Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab or bevacizumab 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, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• •* Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
• •* Subjects with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
• •Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• •* Prior cancer vaccines and cellular immunotherapy are permitted.
• •Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin \[IL\]-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to C1D1
• •Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to C1D1, or anticipated requirement for systemic immunosuppressive medications during the trial
• •* Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
• •* The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed
• •Inadequately controlled hypertension (defined as persistent systolic blood pressure (SBP) \> 150 and/or diastolic blood pressure (DBP) \> 100 mmHg)
• •Prior history of hypertensive crisis or hypertensive encephalopathy
• •Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• •Current or recent (within 10 days of study enrollment) use of aspirin (\> 325 mg/day), clopidogrel (\> 75 mg/day), or current or recent (within 10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes
• •History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
• •Minor surgical procedure within 7 calendar days prior to C1D1
• •History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to enrollment
• •Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• •Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
• •Serious non-healing or dehiscing wound, active ulcer, or untreated or non-healing bone fracture
• •On-going gross hematuria associated with clots