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

• INO-5401 (Biological): INO-5401: A mixture of 3 synthetic plasmids that target Wilms' tumor gene-1 (WT1) antigen, prostate-specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) antigen. IM injection
• INO-9012 (Biological): INO-9012: A synthetic plasmid that expresses human interleukin-12 (IL-12). IM injection.
• Atezolizumab (Drug): IV-Infusion.
• CELLECTRA® 2000 (Device): IM injection.

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) Treatment [Up to approximately 71 months]: An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as any AEs that occurred on or after Day 0. AESIs were toxicities and immune-mediated AEs that may have occurred up to 90 days after the last dose of trial treatment. AESIs were reported by the investigator to the Sponsor within 24 hours after learning of the event.
• Number of Participants With Clinically Significant Changes in Hematological Parameters [Up to approximately 71 months]: Clinically significant changes in hematological parameters were determined based on the investigator's discretion.
• Number of Participants With Clinically Significant Changes in Serum Chemistry Parameters [Up to approximately 71 months]: Clinically significant changes in serum chemistry parameters were determined based on the investigator's discretion.
• Number of Participants With Clinically Significant Changes in Urinalysis Parameters [At baseline, Weeks 3, 6, 9, then every 6 weeks thereafter, up to 71 months]: Clinically significant changes in urinalysis parameters were determined based on the investigator's discretion.
• Antigen-Specific Immune Response [Up to approximately 71 months]: Blood and tissue samples were collected to evaluate the antigen-specific immune response to INO-5401 + INO-9012 in combination with atezolizumab. Planned assessments included: Enzyme Linked Immunosorbent Spot-forming (ELISpot) Assay, Flow cytometry, T cell receptor (TCR) sequencing, ELISA and/or gene expression analysis.
• Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Review in Cohort A [From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months]: ORR was defined as the percentage of participants who had a confirmed complete response (CR) or a partial response (PR). CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters) per RECIST 1.1.

Secondary outcomes

• ORR as Assessed by RECIST Version 1.1 by Investigator Review in Cohort B [From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months]: ORR was defined as the percentage of participants who had a confirmed CR or a PR. CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters) per RECIST 1.1.
• Percentage of Participants With ORR by Immune Response Evaluation Criteria in Solid Tumors (iRECIST) [From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months]: ORR was defined as the percentage of participants who had a confirmed CR or a PR. CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters) per iRECIST.
• Duration of Response (DoR) [From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (approximately 71 months)]: DOR was defined as the time from the date of the first PR or CR to the date of death from any cause or date that progressive disease (PD) was objectively documented, whichever occurred first. CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial (nadir), including baseline. The sum also had to demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
• Progression-Free Survival (PFS) Per RECIST Version 1.1 [From the first dose of study drug to date of PD or death, whichever occurred first (up to approximately 71 months)]: PFS was defined as the time from the date of the start of investigational product treatment until the date of death from any cause or date that progression (+1 day) was objectively documented, whichever occurred first as assessed by RECIST Version 1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial (nadir), including baseline. The sum also had to demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
• PFS Per Immune RECIST (iRECIST) [From Baseline to disease progression or death, whichever occurs first (up to approximately 71 months)]: PFS was defined as the time from the date of the start of investigational product treatment until the date of death from any cause or date that progression (+1 day) was objectively documented, whichever occurred first as assessed by iRECIST Version 1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial (nadir), including baseline. The sum also had to demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
• Overall Survival (OS) [From date of first dose of study drug up to death from any cause, (approximately 71 months)]: OS was defined as the time from the date of the start of investigational product treatment until the date of death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Sign an Informed Consent Form (ICF);
* Have histologically or cytologically documented locally advanced unresectable or metastatic/recurrent urothelial carcinoma (including renal pelvis, ureters, urinary bladder, and urethra);
* For Cohort A: Participants who have radiographically confirmed disease progression during or following treatment with an anti-PD-1/PD-L1 based therapy;
* For Cohort B: No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UCa and ineligible ("unfit") for cisplatin-based chemotherapy;
* Have measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1;
* Have a performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Performance Scale;
* Have life expectancy of >/= 3 months;
* Be willing to provide a tissue sample for pre-treatment intra-tumoral assessment of proinflammatory and immunosuppressive factors;
* Have electrocardiogram (ECG) with no clinically significant findings as assessed by the investigator performed within 28 days prior to first dose;
* Demonstrate adequate hematological, renal, hepatic, and coagulation function;
* 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;
* For male participants: 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:

* 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;
* Documented active or untreated central nervous system (CNS) metastases and/or carcinomatous meningitis;
* 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;
* Prior treatment with CD137 agonists or immune checkpoint blockade therapies;
* Treatment with systemic immunostimulatory agents;
* Treatment with systemic immunosuppressive medication;
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins;
* Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the PD-1/PD-L1 inhibitor formulation;
* Active or history of autoimmune disease or immune deficiency;
* History or any evidence of interstitial lung disease;
* History of human immunodeficiency virus (HIV);
* Active hepatitis B or active hepatitis C;
* Severe infections within 4 weeks prior to enrollment;
* Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 0;
* History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial; interfere with the participant'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 participant to participate in the opinion of the treating investigator;
* Prior allogeneic stem cell or solid organ transplant;
* 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.

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) Treatment (Primary), Count of participants, Participants: Cohort A: Prior Anti-PD-1/PD-L1 27; Cohort B: Naïve Anti-PD-1/PD-L1 8
• Number of Participants With Clinically Significant Changes in Hematological Parameters (Primary), Count of participants, Participants: Cohort A: Prior Anti-PD-1/PD-L1 0; Cohort B: Naïve Anti-PD-1/PD-L1 0
• Number of Participants With Clinically Significant Changes in Serum Chemistry Parameters (Primary), Count of participants, Participants: Cohort A: Prior Anti-PD-1/PD-L1 0; Cohort B: Naïve Anti-PD-1/PD-L1 0
• Number of Participants With Clinically Significant Changes in Urinalysis Parameters (Primary), Count of participants, Participants: Cohort A: Prior Anti-PD-1/PD-L1 0; Cohort B: Naïve Anti-PD-1/PD-L1 0
• Antigen-Specific Immune Response (Primary)
• Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Review in Cohort A (Primary), Number, Percentage of participants: Cohort A: Prior Anti-PD-1/PD-L1 0
• ORR as Assessed by RECIST Version 1.1 by Investigator Review in Cohort B (Secondary), Number, Percentage of participants: Cohort B: Naïve Anti-PD-1/PD-L1 40
• Percentage of Participants With ORR by Immune Response Evaluation Criteria in Solid Tumors (iRECIST) (Secondary), Number, Percentage of participants: Cohort A: Prior Anti-PD-1/PD-L1 0; Cohort B: Naïve Anti-PD-1/PD-L1 40
• Duration of Response (DoR) (Secondary), Median, months: Cohort A: Prior Anti-PD-1/PD-L1 ; Cohort B: Naïve Anti-PD-1/PD-L1 NA (NA to NA)
• Progression-Free Survival (PFS) Per RECIST Version 1.1 (Secondary), Median, months: Cohort A: Prior Anti-PD-1/PD-L1 NA (NA to NA); Cohort B: Naïve Anti-PD-1/PD-L1 NA (NA to NA)
• PFS Per Immune RECIST (iRECIST) (Secondary), Median, months: Cohort A: Prior Anti-PD-1/PD-L1 NA (NA to NA); Cohort B: Naïve Anti-PD-1/PD-L1 NA (NA to NA)
• Overall Survival (OS) (Secondary), Median, months: Cohort A: Prior Anti-PD-1/PD-L1 NA (NA to NA); Cohort B: Naïve Anti-PD-1/PD-L1 NA (NA to NA)

Adverse events

Time frame: Up to approximately 71 months

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-07-01)

• Jeffrey Skolnik, MD, Study director, Inovio Pharmaceuticals