Cervical Intraepithelial Neoplasia
Conditions
Keywords
HSIL, CIN II/III
Brief summary
This is a Phase II study to evaluate the efficacy and safety of a human papilloma virus (HPV) therapeutic vaccine called PepCan (HPV 16 E6 peptides combined with Candida skin testing reagent called Candin®) in adult females over a 12 month time period. As the results from the Phase I trial demonstrated some efficacy against non-16 HPV types, Candin alone will also be tested. Therefore, there will be two treatment arms: (1) PepCan and (2) Candin. Subjects found to be eligible for vaccination will be randomized in a double-blinded fashion at a 1:1 ratio. Each participant will be receiving injections four times with three weeks between injections. Clinical and virological responses will be assessed at 6 and 12 months. Safety will be assessed from the time of enrollment to 12 Month Visit. Immunological assessments will be made at 4 time points (prevaccination, after 2 injections, 6 month after 4 injections and 12 months after 4 vaccinations).
Detailed description
This is a single site Phase II clinical trial of PepCan for treating women with biopsy-proven HSILs (High Grade Intraepithelial Lesions) randomized and double-blinded to two treatment arms. Half of the subjects will receive PepCan, and the other half will receive Candin® alone. The study design closely resembles the latest guidelines for treating young women with HSIL. Study subjects will be patients attending the University of Arkansas for Medical Sciences (UAMS) Obstetrics and Gynecology Clinics with untreated biopsy-proven HSILs and patients referred from other clinics. Four injections (one every 3 weeks) of PepCan or Candin® will be intradermally administered in the extremities. Clinical response will be assessed by comparison of colposcopy-guided biopsy results obtained prior to vaccination and at 12-Month Visit. Safety will be monitored from the time of enrollment through the 12-Month Visit. Blood will be drawn for laboratory testing and immunological analyses (blood test) prior to injection, after the second vaccination, 6 months after the fourth vaccination, and 12 months after the fourth vaccination. Blood will be drawn to aid T-cell analyses (blood draw) after the first and third vaccinations, and possibly at the Optional Follow-Up and/or Optional Loop Electrosurgical Excision Procedure (LEEP) visits. HPV-DNA testing will be performed at Screening and 6- and 12-Month Visits. If a subject has persistent HSIL at the 12-Month Visit or if a subject is withdrawn due to excessive toxicity, she will be given an option to return for a LEEP visit. Alternatively, she may choose to exit the study and be followed by a gynecologist for up to 2 years of observation as recommended before surgical treatment
Interventions
BIOLOGICALPepCan
50 μg peptide + 0.3 mL Candin® per dose administered intradermally in the extremities
BIOLOGICALCandin®
0.3 mL Candin® per dose administered intradermally in the extremities
Sponsors
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
PepCan or Candin randomized at a 1:1 ratio in a double-blinded design.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Aged 18-50 years * Had recent (≤ 60 days) Pap smear result consistent with high grade squamous intraepithelial lesion (HSIL) or cannot rule out HSIL or HSIL on colposcopy-guided biopsy * Untreated for HSIL or Cannot rule out HSIL * Able to provide informed consent * Willingness and able to comply with the requirements of the protocol
Exclusion criteria
* History of disease or treatment causing immunosuppression (e.g., cancer, human immunodeficiency virus (HIV), organ transplant, autoimmune disease) * Being pregnant or attempting to be pregnant within the period of study participation * Breast feeding or planning to breast feed within the period of study participation * Allergy to Candida antigen * History of severe asthma requiring emergency room visit or hospitalization within the past 5 years * History of invasive squamous cell carcinoma of the cervix * History of having received PepCan * If in the opinion of the Principal Investigator or other Investigators, it is not in the best interest of the patient to enter this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Complete Response With the Intention-to-treat (ITT) Analysis | 15 months from time of last vaccination | Histological regression of moderate/severe cervical dysplasia to absence of cervical dysplasia assessed using biopsies (stringent) |
| Number of Subjects With Complete Response With the Per-protocol Analysis | 15 months from time of last vaccination | Histological regression of moderate/severe cervical dysplasia to absence of cervical dysplasia assessed using biopsies (stringent). |
| Number of Subjects With Complete and Partial Responses With the ITT Analysis | 15 months from time of last vaccination | Histological regression of moderate/severe cervical dysplasia to mild dysplasia/no dysplasia (lenient) assessed using biopsies, likely avoiding a need for surgery |
| Number of Subjects With Complete and Partial Responses With the Per-protocol Analysis | 15 months from time of last vaccination | Histological regression of moderate/severe cervical dysplasia to mild dysplasia/no dysplasia (lenient) assessed using biopsies, likely avoiding a need for surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Assessed by Injection-related Adverse Events (AEs) | 15 months from time of last vaccination | Injection-related AEs occurring in \>5% of injections |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PepCan Four injections (one every 3 weeks) of PepCan
PepCan: 50 μg peptide + 0.3 mL Candin® per dose administered intradermally in the extremities | 39 |
| Candin Four injections (one every 3 weeks) of Candin
Candin®: 0.3 mL Candin® per dose administered intradermally in the extremities | 42 |
| Total | 81 |
Baseline characteristics
| Characteristic | PepCan | Total | Candin |
|---|---|---|---|
| ≥ 5 sexual partners | 19 Participants | 49 Participants | 30 Participants |
| Age, Customized <25 years - number (no.) | 6 Participants | 15 Participants | 9 Participants |
| Age, Customized ≥25 years - number (no.) | 33 Participants | 66 Participants | 33 Participants |
| Age, Customized | 31.3 years STANDARD_DEVIATION 6.4 | 31.3 years | 31.4 years STANDARD_DEVIATION 6.1 |
| Albumin < 3.5 g/dL | 1 Participants | 4 Participants | 3 Participants |
| Any children | 27 Participants | 54 Participants | 27 Participants |
| Any college | 20 Participants | 40 Participants | 20 Participants |
| Body mass index <25 kg/m^2 | 18 Participants | 34 Participants | 16 Participants |
| Body mass index ≥25 kg/m^2 - <30 kg/m^2 | 10 Participants | 17 Participants | 7 Participants |
| Body mass index ≥30 kg/m^2 | 11 Participants | 30 Participants | 19 Participants |
| Body mass index | 27.3 kg/m^2 STANDARD_DEVIATION 6.2 | 28.3 kg/m^2 STANDARD_DEVIATION 6.8 | 29.1 kg/m^2 STANDARD_DEVIATION 7.3 |
| Currently smoke | 8 Participants | 17 Participants | 9 Participants |
| Currently use oral contraceptives | 6 Participants | 21 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 23 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 58 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ever smoked | 18 Participants | 33 Participants | 15 Participants |
| Ever used oral contraceptives | 27 Participants | 59 Participants | 32 Participants |
| Histological Diagnosis at Study Entry CIN2 | 10 Participants | 26 Participants | 16 Participants |
| Histological Diagnosis at Study Entry CIN3 and CIN2/3 | 29 Participants | 55 Participants | 26 Participants |
| Human papillomavirus (HPV) prophylactic vaccine | 7 Participants | 14 Participants | 7 Participants |
| Number (No.) of cervical quadrants ≤2 quadrants | 29 Participants | 59 Participants | 30 Participants |
| Number (No.) of cervical quadrants >2 quadrants | 9 Participants | 20 Participants | 11 Participants |
| Number (No.) of cervical quadrants Data not available | 1 Participants | 2 Participants | 1 Participants |
| Number (No.) of cervical quadrants | 1.89 cervical quadrants STANDARD_DEVIATION 1.06 | 1.97 cervical quadrants STANDARD_DEVIATION 1.04 | 2.05 cervical quadrants STANDARD_DEVIATION 1.02 |
| Race/Ethnicity, Customized African American | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 34 Participants | 71 Participants | 37 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 39 Participants | 81 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Total protein < 6.4 g/dL | 3 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 42 |
| other Total, other adverse events | 37 / 39 | 40 / 42 |
| serious Total, serious adverse events | 3 / 39 | 2 / 42 |
Outcome results
Primary
Number of Subjects With Complete and Partial Responses With the ITT Analysis
Histological regression of moderate/severe cervical dysplasia to mild dysplasia/no dysplasia (lenient) assessed using biopsies, likely avoiding a need for surgery
Time frame: 15 months from time of last vaccination
Population: ITT (subjects who were eligible and randomized)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PepCan | Number of Subjects With Complete and Partial Responses With the ITT Analysis | 15 Participants |
| Candin | Number of Subjects With Complete and Partial Responses With the ITT Analysis | 24 Participants |
Primary
Number of Subjects With Complete and Partial Responses With the Per-protocol Analysis
Histological regression of moderate/severe cervical dysplasia to mild dysplasia/no dysplasia (lenient) assessed using biopsies, likely avoiding a need for surgery
Time frame: 15 months from time of last vaccination
Population: Per-protocol (subjects who completed the 12-month visit)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PepCan | Number of Subjects With Complete and Partial Responses With the Per-protocol Analysis | 13 Participants |
| Candin | Number of Subjects With Complete and Partial Responses With the Per-protocol Analysis | 22 Participants |
Primary
Number of Subjects With Complete Response With the Intention-to-treat (ITT) Analysis
Histological regression of moderate/severe cervical dysplasia to absence of cervical dysplasia assessed using biopsies (stringent)
Time frame: 15 months from time of last vaccination
Population: ITT (subjects who were eligible and randomized)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PepCan | Number of Subjects With Complete Response With the Intention-to-treat (ITT) Analysis | 12 Participants |
| Candin | Number of Subjects With Complete Response With the Intention-to-treat (ITT) Analysis | 20 Participants |
Primary
Number of Subjects With Complete Response With the Per-protocol Analysis
Histological regression of moderate/severe cervical dysplasia to absence of cervical dysplasia assessed using biopsies (stringent).
Time frame: 15 months from time of last vaccination
Population: Per-protocol (subjects who completed the 12-month visit)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PepCan | Number of Subjects With Complete Response With the Per-protocol Analysis | 11 Participants |
| Candin | Number of Subjects With Complete Response With the Per-protocol Analysis | 18 Participants |
Secondary
Safety Assessed by Injection-related Adverse Events (AEs)
Injection-related AEs occurring in \>5% of injections
Time frame: 15 months from time of last vaccination
Population: Number of Injections for ITT (subjects who were eligible and randomized)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : Grade 2 | 2 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : All Grades | 37 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : Grade 1 | 9 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : Grade 2 | 1 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : All Grades | 10 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : Grade 1 | 13 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : Grade 2 | 4 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : All Grades | 17 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : Grade 1 | 63 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : Grade 2 | 25 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : All Grades | 88 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : Grade 1 | 35 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : Grade 1 | 19 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : Grade 2 | 0 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : All Grades | 19 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : Grade 1 | 23 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : Grade 2 | 31 Adverse Events |
| PepCan | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : All Grades | 54 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : Grade 2 | 0 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : Grade 2 | 1 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : Grade 2 | 31 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : All Grades | 10 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : All Grades | 57 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : Grade 1 | 3 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : All Grades | 89 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : Grade 2 | 0 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : All Grades | 18 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Fever : All Grades | 3 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Myalgia : Grade 1 | 9 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : Grade 1 | 15 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : Grade 2 | 18 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : Grade 2 | 3 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Nausea : Grade 1 | 18 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Headache : All Grades | 18 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, ≥ 24 h : Grade 1 | 39 Adverse Events |
| Candin | Safety Assessed by Injection-related Adverse Events (AEs) | Injection site reaction, < 24 h : Grade 1 | 58 Adverse Events |