Anal Neoplasm
Conditions
Keywords
High-grade squamous intraepithelial lesions (HSIL), Human papillomavirus (HPV), HPV-16, HPV-18, Anal intraepithelial neoplasia 2 (AIN2), Anal intraepithelial neoplasia 3 (AIN3), Peri-anal intraepithelial neoplasia 2 (PAIN2), Peri-anal intraepithelial neoplasia 3 (PAIN3)
Brief summary
This is a phase 2, open-label efficacy study of VGX-3100 administered by intramuscular (IM) injection followed by electroporation (EP) in adult men and women who are human immunodeficiency virus (HIV) negative with histologically confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesion (HSIL) associated with human papilloma virus (HPV)-16 and/or HPV-18. Approximately 24 participants will receive at least 3 doses of VGX-3100.
Interventions
BIOLOGICALVGX-3100
One milliliter (1 mL) VGX-3100 (deoxyribonucleic acid \[DNA\] plasmids encoding E6 and E7 proteins of HPV types 16 and 18) will be injected IM and delivered by EP using CELLECTRA™ 5PSP on Day 0, Week 4 and Week 12, and potentially Week 40.
DEVICECELLECTRA™ 5PSP
IM injection of VGX-3100 is followed by EP with the CELLECTRA™ 5PSP device.
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
* Negative screening test for HIV-1/2 within 30 days of Dose 1; * Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by polymerase chain reaction (PCR) from HSIL specimen; * Anal tissue specimen/slides for diagnosis must be collected within 10 weeks of first dose of VGX-3100; * At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is histologically-confirmed as HSIL at Screening; * Appropriate candidate for histology collection procedures (i.e. excision or biopsy) as judged by the Investigator; * Female subjects must be post-menopausal, surgically sterile or agree to avoid pregnancy by continued abstinence or use of a contraceptive method with failure rate of less than 1% per year from Screening to one month after last dose of study medication (Week 12 or Week 40) * Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse prior to the study, for the duration of study participation and one month after last dose of study medication. * Normal Screening electrocardiogram (ECG).
Exclusion criteria
* Untreated micro invasive or invasive cancer; * Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and not undergoing medical care and/or treatment for VAIN; * Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and not undergoing medical care and/or treatment for VIN; * Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and not undergoing medical care and/or treatment for CIN; * Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and not undergoing medical care and/or treatment for PIN; * Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; * Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; * Inability to have complete and satisfactory high resolution anoscopic exams (HRAs) * Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of Screening; * Pregnant, breast feeding or considering becoming pregnant within one month following the last dose of study medication; * Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 within 45 days prior to Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; * Immunosuppression as a result of underlying illness or treatment; * History of previous therapeutic HPV vaccination; * Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-3100 dose; * Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of any VGX-3100 dose; * Significant acute or chronic medical illness that could be negatively impacted by the electroporation treated as deemed by the Investigator; * Current or history of clinically significant, medically unstable disease which, in the judgment of the investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results; * Prior major surgery within 4 weeks of Day 0; * Participation in an interventional study with an investigational compound or device within 4 weeks of signing the ICF; * Any illness or condition that in the opinion of the Investigator may affect the safety of the subject or the evaluation of any study endpoint.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL and no Evidence of HPV-16/18 at Week 36 | Week 36 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Local and Systemic Treatment-emergent Adverse Event (TEAE) During 7 Days Following Each Dose | 7 days following each dose: Day 0 (Days 0 to 7), Week 4 (Days 22 to 28), Week 12 (Days 78 to 84), and Week 40 (Days 274 to 280) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug. |
| Number of Participants With at Least One Adverse Event (AE) | From first injection up to Week 88 | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal HSIL at Week 36 | Week 36 | — |
| Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal and/or Peri-Anal Tissue by Type-Specific HPV Testing at Week 36 | Week 36 | — |
| Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal Swab by Specific HPV Testing at Week 36 | Week 36 | — |
| Percentage of Participants With no Progression of Anal or Anal/Peri-Anal HSIL to Carcinoma From Baseline to Week 36 | From Baseline to Week 36 | — |
| Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 | From Baseline to Weeks 36, 64, and 88 | — |
| Mean Change From Baseline in Frequency of HPV-16/17 E6/E7-specific CD8+/CD137+ Peripheral Blood Mononuclear Cells (PBMCs) That Were Perforin Positive at Week 15 | Baseline and Week 15 | PBMCs were isolated from whole blood samples. The assessment of cellular immune activity occurred via the application Flow Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay examined cluster of differentiation (CD)8/CD137 cellular markers and Perforin (proteins involved in lytic degranulation and cytotoxic potential) intracellular marker. The frequency was presented as number of perforin-positive CD8 i.e., CD8+/ CD137+ PBMCs cells per million CD8+/ CD137+ PBMCs cells. |
| Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL or no Evidence of HPV-16/18 at Week 36 | Week 36 | — |
| Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal Low-Grade Squamous Intraepithelial Lesion (LSIL) or HSIL at Week 36 | Week 36 | — |
Other
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in the Size of Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 | From Baseline to Weeks 36, 64, and 88 |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Canada and the United States from 15 May 2018 to 16 June 2020.
Pre-assignment details
A total of 48 participants were screened out of which 23 were enrolled to receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| VGX-3100 Adult participants who were HIV negative with histologically confirmed anal or anal/peri-anal HSIL associated with HPV-16 and/or 18, received four 6 mg doses of VGX-3100 as an IM injection on Day 0, Week 4, Week 12, and Week 40 followed immediately by EP using the CELLECTRA™ 5PSP device. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | VGX-3100 |
|---|---|
| Age, Continuous | 46 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants |
| Race/Ethnicity, Customized Race White | 16 Participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 23 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL and no Evidence of HPV-16/18 at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL and no Evidence of HPV-16/18 at Week 36 | 9.1 percentage of participants |
p-value: 0.8633Clopper-Pearson
Secondary
Mean Change From Baseline in Frequency of HPV-16/17 E6/E7-specific CD8+/CD137+ Peripheral Blood Mononuclear Cells (PBMCs) That Were Perforin Positive at Week 15
PBMCs were isolated from whole blood samples. The assessment of cellular immune activity occurred via the application Flow Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay examined cluster of differentiation (CD)8/CD137 cellular markers and Perforin (proteins involved in lytic degranulation and cytotoxic potential) intracellular marker. The frequency was presented as number of perforin-positive CD8 i.e., CD8+/ CD137+ PBMCs cells per million CD8+/ CD137+ PBMCs cells.
Time frame: Baseline and Week 15
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VGX-3100 | Mean Change From Baseline in Frequency of HPV-16/17 E6/E7-specific CD8+/CD137+ Peripheral Blood Mononuclear Cells (PBMCs) That Were Perforin Positive at Week 15 | 4.491 cells/million T cells + PBMCs | Standard Deviation 4.9686 |
Secondary
Number of Participants With at Least One Adverse Event (AE)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: From first injection up to Week 88
Population: Safety population included all participants who received at least 1 dose of VGX-3100+EP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VGX-3100 | Number of Participants With at Least One Adverse Event (AE) | 23 Participants |
Secondary
Number of Participants With at Least One Local and Systemic Treatment-emergent Adverse Event (TEAE) During 7 Days Following Each Dose
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug.
Time frame: 7 days following each dose: Day 0 (Days 0 to 7), Week 4 (Days 22 to 28), Week 12 (Days 78 to 84), and Week 40 (Days 274 to 280)
Population: Safety population included all participants who received at least 1 dose of VGX-3100+EP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VGX-3100 | Number of Participants With at Least One Local and Systemic Treatment-emergent Adverse Event (TEAE) During 7 Days Following Each Dose | 21 Participants |
Secondary
Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal HSIL at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal HSIL at Week 36 | 13.6 percentage of participants |
Secondary
Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal Low-Grade Squamous Intraepithelial Lesion (LSIL) or HSIL at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal Low-Grade Squamous Intraepithelial Lesion (LSIL) or HSIL at Week 36 | 9.1 percentage of participants |
Secondary
Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal and/or Peri-Anal Tissue by Type-Specific HPV Testing at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal and/or Peri-Anal Tissue by Type-Specific HPV Testing at Week 36 | 45.5 percentage of participants |
Secondary
Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal Swab by Specific HPV Testing at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal Swab by Specific HPV Testing at Week 36 | 31.8 percentage of participants |
Secondary
Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL or no Evidence of HPV-16/18 at Week 36
Time frame: Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL or no Evidence of HPV-16/18 at Week 36 | 50.0 percentage of participants |
Secondary
Percentage of Participants With no Progression of Anal or Anal/Peri-Anal HSIL to Carcinoma From Baseline to Week 36
Time frame: From Baseline to Week 36
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VGX-3100 | Percentage of Participants With no Progression of Anal or Anal/Peri-Anal HSIL to Carcinoma From Baseline to Week 36 | 100 percentage of participants |
Secondary
Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88
Time frame: From Baseline to Weeks 36, 64, and 88
Population: mITT population included all participants who received at least 1 dose of VGX-3100+EP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis. 'Number analyzed' indicates the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VGX-3100 | Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 | Percent Change From Baseline at Week 36 | -14.2 percent change | Standard Deviation 41.93 |
| VGX-3100 | Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 | Percent Change From Baseline at Week 64 | -3.3 percent change | Standard Deviation 37.91 |
| VGX-3100 | Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 | Percent Change From Baseline at Week 88 | -40.6 percent change | Standard Deviation 46.77 |
Other Pre-specified
Percent Change From Baseline in the Size of Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88
Time frame: From Baseline to Weeks 36, 64, and 88