Brief Title: GU-114: Overcoming Checkpoint Inhibitor Resistance With Epigenetic Therapy in Urothelial Cancer

PRIMARY OUTCOMES

Primary Outcome 1 - Measure:

Primary Outcome 1 - Timeframe: N/A

CONDITION

• Urothelial Carcinoma

ELIGIBILITY

Inclusion Criteria:
1. Patients must have histologically confirmed urothelial carcinoma that is advanced or metastatic.

- 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 urine)

- * 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 consent document

- 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.
Exclusion Criteria:
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 shorter.

- 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 Frediricia's correction.

- 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 study treatment.

- 16. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis)

- 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 drugs.

- 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 study.

- 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 study requirements.

- 23. Known HIV-positive patients on combination antiretroviral therapy are ineligible.

- 24. Known history of HBV or HCV infection.

- 25. Pregnant or breast feeding.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

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Role: N/A

Affiliation: N/A

Overall Contact

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LOCATION