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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
35
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: A synthetic plasmid that expresses human interleukin-12 (IL-12). IM injection.
IV-Infusion.
IM injection.
Mayo Clinic Cancer Center
Phoenix, Arizona, United States
H. Lee Moffitt Cancer Center & Research Institute, Inc.
Tampa, Florida, United States
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Washington University School of Medicine in St. Louis
St Louis, Missouri, United States
New York University Langone Medical Center - Perlmutter Cancer Center
New York, New York, United States
Columbia University, Herbert Irving Comprehensive Cancer Center
New York, New York, United States
University of North Carolina School of Medicine
Chapel Hill, North Carolina, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Greenville Memorial Hospital
Greenville, South Carolina, United States
...and 1 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From date of treatment start until date of first PD or death (whichever occurred first), up to approximately 71 months
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: From date of first dose of study drug up to death from any cause, (approximately 71 months)