This is a single arm Phase II study with a safety run-in to identify the recommended phase II
dose of the combination therapy of atezolizumab and guadecitabine. Patients with
recurrent/advanced urothelial carcinoma (stage IV) who had previously progressed on
check-point inhibitor therapy with PD-1 or PD-L1 targeting agents are eligible for this
study. After a dose that is safe and tolerable has been established, a dose expansion phase
(Phase II) will begin. This study will enroll a total of 4 to 53 patients depending upon the
number of patients treated in the safety run-in phase and the number of subjects replaced
during the phase II portion.
1. Patients must have histologically confirmed urothelial carcinoma that is advanced or
2. 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.
3. Patient must agree to provide fresh biopsy specimens and peripheral blood samples at
the time of screening and during the study.
4. 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.
5. Age > 18 years.
6. ECOG performance status ≤ 2
7. Life expectancy ≥ 12 weeks
8. 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
- INR or PTT/PT ≤ 1.5 ULN unless patient is on stable therapeutic dose of warfarin
9. Ability to understand and willingness to sign a written informed consent and HIPAA
10. 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.
1. Patients who have had anti-cancer therapy within 2 weeks prior to entering the study.
2. Patients receiving any other investigational agents
3. 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.
4. Patients with active auto-immune disease requiring immunosuppressive medication.
5. 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
6. 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.
7. Patients with active malignancies in addition to urothelial carcinoma.
8. Patients with prior treatment with hypomethylating agents.
9. History of leptomeningeal disease
10. Prior allogeneic stem cell or solid organ transplant.
11. Uncontrolled effusion, pericardial effusion, or ascites requiring recurrent drainage
procedures (once monthly or more frequently)
12. Uncontrolled symptomatic hypercalcemia (>1.5mmol/L ionized calcium or calcium >
12mg/dl or corrected serum calcium > ULN)
13. Mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3 ECGs using
14. 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.
15. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to the start of the
16. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease,
17. History of severe allergic, anaphylactic or hypersensitivity reactions to chimeric or
humanized antibodies or fusion proteins.
18. 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.
19. Active tuberculosis
20. Known hypersensitivity to Chinese hamster ovary cell products or any of the study
21. 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
22. 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
23. Known HIV-positive patients on combination antiretroviral therapy are ineligible.
24. Known history of HBV or HCV infection.
25. Pregnant or breast feeding.