INO-5401 + INO-9012 in Combination With Atezolizumab in Locally Advanced Unresectable or Metastatic/Recurrent Urothelial Carcinoma

Inclusion Criteria:

1. Sign an Informed Consent Form (ICF);
2. Have histologically or cytologically documented locally advanced unresectable or metastatic/recurrent urothelial carcinoma (including renal pelvis, ureters, urinary bladder, and urethra);
3. For Cohort A: Subjects who have radiographically confirmed disease progression during or following treatment with an anti-PD-1/PD-L1 based therapy;
4. For Cohort B: No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UCa and ineligible ("unfit") for cisplatin-based chemotherapy;
5. Have measurable disease, as defined by RECIST version 1.1;
6. Have a performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Performance Scale;
7. Have life expectancy of >/= 3 months;
8. Be willing to provide a tissue sample for pre-treatment intra-tumoral assessment of proinflammatory and immunosuppressive factors;
9. Have electrocardiogram (ECG) with no clinically significant findings as assessed by the investigator performed within 28 days prior to first dose;
10. Demonstrate adequate hematological, renal, hepatic, and coagulation function;
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study treatment;
12. For male subjects: agreement not to father a child. Participants must be surgically sterile (e.g, vasectomy) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study treatment.

Exclusion Criteria:

1. Any approved anti-cancer therapy including chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to trial Day 0 as well as current participation or recipient of treatment on a clinical trial within 28 days prior to Day 0;
2. Documented active or untreated central nervous system (CNS) metastases and/or carcinomatous meningitis;
3. Malignancies other than UCa within 3 years prior to Day 0, with the exception of those with negligible risk of metastasis or death treated with expected curative outcome;
4. Prior treatment with CD137 agonists or immune checkpoint blockade therapies;
5. Treatment with systemic immunostimulatory agents;
6. Treatment with systemic immunosuppressive medication;
7. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins;
8. Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the PD-1/PD-L1 inhibitor formulation;
9. Active or history of autoimmune disease or immune deficiency;
10. History or any evidence of interstitial lung disease;
11. History of human immunodeficiency virus (HIV);
12. Active hepatitis B or active hepatitis C;
13. Severe infections within 4 weeks prior to enrollment;
14. Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 0;
15. History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial; interfere with the subject's participation for the full duration of the trial, or is negatively impacted by EP treatment, or is not in the best interest of the subject to participate in the opinion of the treating investigator;
16. Prior allogeneic stem cell or solid organ transplant;
17. Uncontrolled tumor-related pain; pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures; or, hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.