Atezolizumab and Guadecitabine in Treating Patients with Advanced or Metastatic Urothelial Cancer

Inclusion Criteria

• Patients must have histologically confirmed urothelial carcinoma that is advanced or metastatic
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v.) 1.1 and >= 1 site safe for biopsy
• Patient must agree to provide fresh biopsy specimens and peripheral blood samples at the time of screening and during the study
• Patients must have received or be ineligible for platinum based chemotherapy and must have received at least one line of therapy with a PD-L1 or PD-1 targeting agent
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Life expectancy >= 12 weeks
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin > 9 g/dl (blood transfusion is allowed to meet the eligibility criteria as long as post transfusion hemoglobin is maintained at >= 9.0 g/dL for 7 days or longer)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) or direct bilirubin =< ULN for participants with total bilirubin > 1.5 x ULN
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times institutional normal limits
• Creatinine within normal institutional limits OR creatinine clearance >= 30 Ml/min (Cockcroft-Gault formula or measured with 24 hour [h] urine)
• International normalized ratio (INR) or partial thromboplastin time (PTT)/prothrombin time (PT) =< 1.5 ULN, unless the patient is on stable therapeutic dose of warfarin
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
• Women of child bearing potential and men must agree to remain abstinent or use adequate contraception (failure rate < 1%) for the duration of study and for 90 days after the completion of the therapy

Exclusion Criteria

• Patients who have had anti-cancer therapy within 2 weeks prior to entering the study
• Patients receiving any other investigational agents
• Patients with active or untreated central nervous system (CNS) disease; patients previously treated for CNS disease must be asymptomatic and must not be using steroids for at least 4 weeks prior to starting the study treatment
• Patients with active auto-immune disease requiring immunosuppressive medication
• Patients treated with systemic immunostimulatory agents (such as interferons, IL 12) within 6 weeks of the start of the treatment or 5 half-lives of the drug, whichever is shorter
• Treatment with systemic corticosteroids within 2 weeks prior to the start of the treatment; patients that require inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, mineralocorticoids are allowed
• Patients with active malignancies in addition to urothelial carcinoma
• Patients with prior treatment with hypomethylating agents
• History of leptomeningeal disease
• Prior allogeneic stem cell or solid organ transplant
• Uncontrolled effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dl or corrected serum calcium > ULN)
• Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiography (ECG)s using Frediricia’s correction
• Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1 except for endocrine adverse events (AEs) managed with replacement therapy; any other AEs unresolved toxicities grade 2 or more from previous anti-cancer therapy, except alopecia, peripheral neuropathy or non-clinically significant lab abnormalities
• Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to the start of the study treatment
• Documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis)
• History of severe allergic, anaphylactic or hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Active tuberculosis
• Known hypersensitivity to Chinese hamster ovary cell products or any of the study drugs
• Administration of a live, attenuated vaccine within 4 weeks of the start of treatment or anticipation that such a live, attenuated vaccine will be required during the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Pregnant or breast feeding