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

An Open-Label, Multi-Center Trial of INO-5401 + INO-9012 in Combination With Atezolizumab in Subjects With Locally Advanced Unresectable or Metastatic/Recurrent Urothelial Carcinoma

This was a Phase I/IIA, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of INO-5401 + INO-9012 delivered by intramuscular (IM) injection followed by electroporation (EP), in combination with atezolizumab in participants with locally advanced unresectable or metastatic/recurrent Urothelial Carcinoma (UCa). The trial population was divided into two cohorts: Cohort A: participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti-programmed death receptor-1/programmed death receptor ligand-1 (anti-PD-1/PD-L1) therapy; Cohort B: participants with locally advanced unresectable or metastatic/recurrent UCa, who were treatment naïve and ineligible for cisplatin-based chemotherapy. A safety run-in was performed using a modified rolling six design, enrolling up to 6 participants (safety analysis participants) from Cohort A.

Study Overview

• Status: Completed
• Conditions: Urothelial Carcinoma
• Intervention / Treatment: Biological: INO-5401; Biological: INO-9012; Drug: Atezolizumab; Device: CELLECTRA® 2000

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute, Inc.
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School Of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine in St. Louis
  • New York
    • New York, New York, United States, 10032
      • Columbia University, Herbert Irving Comprehensive Cancer Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center - Perlmutter Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Greenville Memorial Hospital
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Melanoma and Skin Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: Prior Anti-PD-1/PD-L1; Participants with locally advanced unresectable or metastatic/recurrent UCa, who had confirmed disease progression during or following treatment with anti- programmed death receptor-1/ programmed cell death-ligand 1 (PD-1/PD-L1) therapy received INO-5401 9 milligrams (mg) and INO-9012 1 mg, intramuscular (IM) injection, followed by electroporation (EP) by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, intravenous (IV) infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.	Biological: INO-5401; 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; Biological: INO-9012; INO-9012: A synthetic plasmid that expresses human interleukin-12 (IL-12). IM injection.; Drug: Atezolizumab; IV-Infusion.; Device: CELLECTRA® 2000; IM injection.
Experimental: Cohort B: Naïve Anti-PD-1/PD-L1; Participants with locally advanced unresectable or metastatic/recurrent UCa who are treatment naïve and ineligible for cisplatin-based chemotherapy received INO-5401 9 mg and INO-9012 1 mg, IM injection, followed by EP by CELLECTRA® 2000 device, every 3 weeks until Week 9, then every 6 weeks for 6 more doses (until Week 45), thereafter every 12 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator in combination with atezolizumab 1200 mg, IV infusion, every 3 weeks, until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator.	Biological: INO-5401; 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; Biological: INO-9012; INO-9012: A synthetic plasmid that expresses human interleukin-12 (IL-12). IM injection.; Drug: Atezolizumab; IV-Infusion.; Device: CELLECTRA® 2000; IM injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs) Treatment	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.	Up to approximately 71 months
Number of Participants With Clinically Significant Changes in Hematological Parameters	Clinically significant changes in hematological parameters were determined based on the investigator's discretion.	Up to approximately 71 months
Number of Participants With Clinically Significant Changes in Serum Chemistry Parameters	Clinically significant changes in serum chemistry parameters were determined based on the investigator's discretion.	Up to approximately 71 months
Number of Participants With Clinically Significant Changes in Urinalysis Parameters	Clinically significant changes in urinalysis parameters were determined based on the investigator's discretion.	At baseline, Weeks 3, 6, 9, then every 6 weeks thereafter, up to 71 months
Antigen-Specific Immune Response	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.	Up to approximately 71 months
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Review in Cohort A	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.	From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR as Assessed by RECIST Version 1.1 by Investigator Review in Cohort B	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.	From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months
Percentage of Participants With ORR by Immune Response Evaluation Criteria in Solid Tumors (iRECIST)	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.	From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months
Duration of Response (DoR)	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.	From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (approximately 71 months)
Progression-Free Survival (PFS) Per RECIST Version 1.1	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.	From the first dose of study drug to date of PD or death, whichever occurred first (up to approximately 71 months)
PFS Per Immune RECIST (iRECIST)	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.	From Baseline to disease progression or death, whichever occurs first (up to approximately 71 months)
Overall Survival (OS)	OS was defined as the time from the date of the start of investigational product treatment until the date of death from any cause.	From date of first dose of study drug up to death from any cause, (approximately 71 months)

Collaborators and Investigators

• Sponsor: Inovio Pharmaceuticals
• Investigators: Study Director: Jeffrey Skolnik, MD, Inovio Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2018
• Primary Completion (Actual): May 9, 2025
• Study Completion (Actual): May 9, 2025

Study Registration Dates

• First Submitted: April 11, 2018
• First Submitted That Met QC Criteria: April 11, 2018
• First Posted (Actual): April 19, 2018

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: September 1, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; atezolizumab; rocakinogene sifuplasmid
• Other Study ID Numbers: UCa-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes