Respiratory Papillomatosis
Conditions
Keywords
Human papilloma virus (HPV)
Brief summary
This is a Phase 1/2 open-label, multicenter trial to evaluate the safety, tolerability, immunogenicity, and efficacy of INO-3107 in participants with human papilloma virus type 6 (HPV-6) and/or type 11 (HPV-11)-associated recurrent respiratory papillomatosis (RRP). The trial population will include participants who have been diagnosed with either Juvenile-Onset RRP (J-O RRP) as defined by age at first diagnosis \<12 years or with Adult- Onset RRP (A-O RRP) as defined by age at first diagnosis ≥12 years. A safety run-in will be performed with up to six participants with a one week waiting period between each enrolled participant.
Interventions
DRUGINO-3107
INO-3107 administered by IM injection.
DEVICECELLECTRA® 2000
CELLECTRA® 2000 device used for EP following IM delivery of INO-3107.
Sponsors
Inovio Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically-documented HPV-6- or HPV-11-positive respiratory papilloma or documentation of low-risk positive HPV using a Sponsor approved HPV-6/11 type-specific assay * Requirement for frequent RRP intervention to remove or resect respiratory papilloma, as defined as at least two RRP surgical (including laser) interventions in the year prior to and including Day 0 * Must be an appropriate candidate for upcoming surgical intervention as per Investigator judgment and RRP Staging Assessment score * Adequate bone marrow, hepatic, and renal function * Participants must meet one of the below requirements: * Be of non-child bearing potential (≥12 months of non-therapy-induced amenorrhea, confirmed by follicle-stimulating hormone \[FSH\], if not on hormone replacement) * Be surgically sterile (vasectomy in males or absence of ovaries and/or uterus in females) * Agree to use one highly effective or combined contraceptive methods that result in a failure rate of \<1% per year during the treatment period and at least through week 12 after last dose * Agree to abstinence from penile-vaginal intercourse, when this is the participant's preferred and usual lifestyle Key
Exclusion criteria
* Recipient of therapy directed towards RRP disease (other than surgery or ablation) including but not limited to anti-virals (including cidofovir), radiation, chemotherapy, anti-angiogenic therapy (including bevacizumab), prophylactic HPV vaccination (including Gardasil) as therapeutic intervention, or therapy with an experimental agent within 3 months prior to Day 0 * Ongoing or recent (within 1 year) evidence of autoimmune disease that required treatment with systemic immunosuppressive treatments, with the exception of: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that requires only hormone replacement, or psoriasis that does not require systemic treatment * Diagnosis of immunodeficiency or treatment with systemic immunosuppressive therapy within 28 days prior to the first dose of trial treatment, including systemic corticosteroids * High risk of bleeding or require the use of anticoagulants for management of a known bleeding diathesis * Recipient of any live virus vaccine within 4 weeks prior to the first dose of trial treatment or any non-live vaccine within two weeks prior to the first dose of trial treatment * History of clinically significant, medically unstable disease which, in the judgment of the Investigator, would jeopardize the safety of the participant, interfere with trial assessment or evaluation, or otherwise impact the validity of the trial results * Fewer than two acceptable sites are available for IM injection considering the deltoid and anterolateral quadriceps muscles. Study treatment should not be given within 2 centimeters (cm) of a tattoo, keloid or hypertrophic scar. If there is implanted metal, implanted device, within the same limb the use of the deltoid muscle on the same side of the body is excluded * Prisoners or participants who are compulsory detained (involuntary incarceration) for treatment of either a psychiatric or physical (i.e. infectious disease) illness * Any medical or psychological or non-medical condition that might interfere with the participation or safety of the participant, as determined by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose of study drug through 30 days following the last dose (approximately up to Week 13) | An adverse event (AE) was 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. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly or birth defect, or was considered an important medical event. TEAEs were defined for this trial as any AEs that occurred following Day 0 following administration of study drug (IM + EP), until 30 days following the last dose. TEAEs included both serious and non-serious TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Recurrent Respiratory Papillomatosis (RRP) Surgical Interventions in One Year Following Day 0, Compared to One Year Prior to Day 0 | Up to Week 52 | — |
| Percentage of Participants by Percent Reduction in RRP Surgical Interventions Post Baseline Compared to Prior Year | Up to Week 52 | — |
| Change From Baseline in RRP Staging Assessment Scores Over Time | Baseline, Weeks 6, 11, 26, and 52 | RRP staging assessment score was determined using a modified Derkay staging tool. It included both a subjective functional assessment of clinical parameters and an anatomic assessment of disease distribution. The anatomic score was then used in combination with the functional score to measure an individual participant's clinical course and response to the therapy over time. The score ranges from 0-179, where a higher score indicates worse disease. Baseline is defined as the most recent measurement prior to the first (Day 0) dose. Total Site Score + Total Symptom Score = Total Clinical Score. |
| Change in Interferon-gamma Enzyme-Linked Immunosorbent Spot (IFN-γ ELISpot) Response Magnitude for IFN-γ Secreting Cells in Peripheral Blood Mononuclear Cells (PBMCs) | Baseline, Weeks 6, 9, 11, 26, and 52 | Whole blood samples were collected and PBMCs were isolated to be tested for T-lymphocytes producing interferon-gamma (IFN-γ) in response to the human papilloma virus (HPV) types 6E6+6E7, and 11E6+11E7 antigens. The antigen-specific cellular immune response to INO-3107 was measured in spot-forming units per million peripheral blood mononuclear cells (SFU/10\^6, PBMC) using ELISpot for this outcome measure (OM). |
| Change in Flow Cytometry Response Magnitude for T-cell Phenotype and Lytic Potential in PBMCs | Baseline, Weeks 6, 9, 11, 26, and 52 | Cellular immune activity was measured using flow cytometry for the purposes of performing a lytic granule loading assay, which analyzed the intracellular markers involved in lytic degranulation and cytotoxic potential: Granzyme A (GrzA), Granzyme B (GrzB), Granulysin, and Perforin (Prf). Subtypes of CD8 T-cells: CD8 HPV-6 CD38+GrzA+GrzB+Prf+, CD8 HPV-11 CD38+GrzA+GrzB+Prf+, CD8 HPV-6 Ki67+GrzA+GrzB+Prf+, and CD8 HPV-11 Ki67+GrzA+GrzB+Prf+, subtypes of CD4 T-cells - CD4 HPV-6 CD38+, CD4 HPV-11 CD38+, CD4 HPV-6 Ki67+, and CD4 HPV-11 Ki67+ are reported. |
| Pro-inflammatory Elements in Resected Tumor Tissues Assessed by Ribo-nucleic Acid (RNA) Sequencing | Baseline, up to Week 52 | Pro-inflammatory elements:granulysin (GNLY),C-X-C motif chemokine receptor 6(CXCR6),C-C motif chemokine receptor 5(CCR5),CXCR3, granzyme A(GZMA),interferon regulatory factor1(IRF1),integrin subunit alpha 1(ITGA1),lymphocyte-specific protein tyrosine kinase(LCK),natural killer cell granule protein 7(NKG7),perforin-1(PRF1),eomesodermin(EOMES),CD3 delta subunit of T cell receptor complex(CD3D),CD3 epsilon subunit of T cell receptor complex(CD3E),\&CD8 subunit alpha(CD8A) in papilloma tissues are reported. Reads that mapped to transcript of each gene were counted to measure expression levels for genes from each sample. Raw counts per gene were generated. Counts per million (CPM) mapped reads were calculated \& globally normalized across samples using trimmed mean of M values (TMM). |
Countries
United States
Contacts
STUDY_DIRECTORJeffrey Skolnik, MD
Inovio Pharmaceuticals
Participant flow
Recruitment details
Participants were enrolled in this study from 07 October 2020 to 15 December 2022. Data for all participants, including those in the safety run-in, is included in the reported arms.
Pre-assignment details
A total of 32 participants with recurrent respiratory papillomatosis (RRP) were enrolled and treated in this study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 15.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 18 | 0 / 8 | 0 / 32 |
| other Total, other adverse events | 2 / 6 | 12 / 18 | 6 / 8 | 20 / 32 |
| serious Total, serious adverse events | 0 / 6 | 0 / 18 | 1 / 8 | 1 / 32 |
Outcome results
None listed