Atezolizumab + Guadecitabine in Patients With Checkpoint Inhibitor Refractory or Resistant Urothelial Carcinoma

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 RECIST criteria 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.
• Age > 18 years.
• ECOG performance status ≤ 2
• Life expectancy ≥ 12 weeks
• Patients must have normal organ and marrow function as defined below

• 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 ≤ 2.5 x institutional upper limit of normal (ULN).
• AST/ALT (SGOT/SGPT) < 2.5 times institutional normal limits unless liver metastases are present in which case AST and ALT must be ≤ 5 x IULN.
• Creatinine within normal institutional limits OR
• Creatinine clearance > 30 Ml/min (Cockcroft-Gault formula or measured with 24h urine)
• INR or PTT/PT ≤ 1.5 ULN unless patient is on stable therapeutic dose of warfarin
• Ability to understand and willingness to sign a written informed consent and 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 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 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 (>1.5mmol/L ionized calcium or calcium > 12mg/dl or corrected serum calcium > ULN)
• Mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3 ECGs 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 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.
• Active or prior 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.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterations), drug-induced pneumonitis or idiopathic pneumonitis or evidence of interstitial lung disease or active non-infectious pneumonitis.
• 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 HIV-positive patients on combination antiretroviral therapy are ineligible.
• Known history of HBV or HCV infection.
• Pregnant or breast feeding.