Cervical Intraepithelial Neoplasia (CIN 2/3), HPV16 Positive
Conditions
Keywords
high grade cervical dysplasia, treatment vaccine, therapeutic, HPV, DNA vaccine, gene therapy, gene gun, pre-cancerous
Brief summary
This study will test the efficacy and safety of different routes of administration of a DNA vaccine in patients with HPV16+ CIN2/3. Subjects will be enrolled in one of six treatment groups. Subjects enrolled in the first two groups will receive vaccination intradermally with a needle-free delivery device. Subjects enrolled in groups 3 and 4 will receive vaccination intramuscularly. Subjects enrolled in groups 5 and 6 will receive vaccine intralesionally.
Detailed description
Primary Objectives * To evaluate the feasibility and toxicity of vaccination in women with CIN2/3 caused by HPV16 * To evaluate the effect of vaccination on histology * To compare immunogenicity of three different routes of administration: intradermal (ID), intramuscular (IM), intralesional (IL). Secondary Objectives: * To evaluate changes in HPV viral load * To evaluate the cellular immune response to vaccination * To evaluate the humoral immune response to vaccination * To evaluate local tissue immune response * To correlate measures of immune response with clinical response * To correlate measures of immune response with those observed in the preclinical model
Interventions
BIOLOGICALDNA vaccination
vaccination with pNGVL4a-CRT/E7(detox)
DEVICEGene gun vaccine
8 micrograms (group 1) or 16 micrograms (group 2)
BIOLOGICALintramuscular vaccination
1mg (group 3) or 3mg (group 4) of pNGVLra-CRT/E7(detox) administered intramuscularly
BIOLOGICALintra-lesional vaccine administration
1mg (group 5) or 3mg (group 6) of pNGVL4a-CRT/E7(detox)administered intra-lesionally
PROCEDUREtherapeutic resection of the lesion
at week 15, all residual lesions will be resected
DRUGimiquimod
imiquimod applied to the cervix by the physician
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* patients with high grade cervical intraepithelial lesions (CIN2/3) * patients whose lesions are HPV16+ * patients who are age 18 or older * patients who are able to give informed consent * patients who are immunocompetent * patients who are not pregnant, committed to using adequate contraception if of childbearing age * patients who have a minimum hemoglobin level of 9
Exclusion criteria
* Patients with cytologic evidence of glandular dysplasia * Patients with cytologic evidence of adenocarcinoma in situ * Patients who are pregnant * Patients with an active autoimmune disease * Patients who are taking immunosuppressive medication * Patients with concurrent malignancy except for nonmelanoma skin lesions * Patients who have an allergy to gold. * Patients with any evidence of damaged skin, or moles, scars, tattoos or marks at the proposed site(s) of administration that might interfere with the interpretation of local skin reactions. * History or evidence of a physician-diagnosed chronic or recurrent inflammatory skin disease (e.g. psoriasis, eczema, atopic dermatitis, hypersensitivity) at the proposed site of administration in the past 5 years. * Patients who have an active autoimmune disease or history of autoimmune disease requiring medical treatment with systemic immunosuppressants, including: inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemic, or immune thrombocytopenia, rheumatoid arthritis, SLE, and Sjogren's syndrome, sarcoidosis. Asthma or COPD that does not require systemic corticosteroids or routine use of inhaled steroids is acceptable * Patients who have received prior chrysotherapy (administration of gold salts to treat rheumatoid arthritis). * Patients with a history of arterial or venous thrombosis * Patients with non-healed wounds. * Patients with a history of keloid formation ( ID delivery group only) * Patients with a history of hepatitis B with persistent infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Related Serious Adverse Events | 9 months | Presence of intervention-related serious adverse events as defined by CTCAE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absence of CIN2/3 Lesion by Week 15 | 15 weeks | Number of participants with no CIN2/3 lesion at the week 15 visit |
Countries
United States
Participant flow
Pre-assignment details
132 subjects signed consents to be screened for eligibility * 93 subjects signed consents, but did not meet the eligibility criteria to start the study (screen failures) * 39 subjects were assigned to a treatment group in the study
Participants by arm
| Arm | Count |
|---|---|
| PMED Delivery - Groups 1 and 2 Subjects will receive pNGVL4a-CRT/E7(detox) via gene gun at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
DNA vaccination: vaccination with pNGVL4a-CRT/E7(detox)
Gene gun vaccine: 8 micrograms (group 1) or 16 micrograms (group 2)
therapeutic resection of the lesion: at week 15, all residual lesions will be resected | 10 |
| IM Injections - Groups 5 and 6 Subjects will receive pNGVL4a-CRT/E7(detox) intramuscularly at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
DNA vaccination: vaccination with pNGVL4a-CRT/E7(detox)
intramuscular vaccination: 1mg (group 3) or 3mg (group 4) of pNGVLra-CRT/E7(detox) administered intramuscularly
therapeutic resection of the lesion: at week 15, all residual lesions will be resected | 11 |
| Intralesional Delivery - Group 3 and 4 Subjects will receive pNGVL4a-CRT/E7(detox) intra-mucosally at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
DNA vaccination: vaccination with pNGVL4a-CRT/E7(detox)
intra-lesional vaccine administration: 1mg (group 5) or 3mg (group 6) of pNGVL4a-CRT/E7(detox)administered intra-lesionally
therapeutic resection of the lesion: at week 15, all residual lesions will be resected | 11 |
| Intralesional Delivery + Imiquimod - Group 7 Subjects will receive pNGVL4a-CRT/E7(detox) intra-mucosally and imiquimod applied to the cervix at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
DNA vaccination: vaccination with pNGVL4a-CRT/E7(detox)
intra-lesional vaccine administration: 1mg (group 5) or 3mg (group 6) of pNGVL4a-CRT/E7(detox)administered intra-lesionally
therapeutic resection of the lesion: at week 15, all residual lesions will be resected
imiquimod: imiquimod applied to the cervix by the physician | 7 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | PMED Delivery - Groups 1 and 2 | Total | Intralesional Delivery + Imiquimod - Group 7 | Intralesional Delivery - Group 3 and 4 | IM Injections - Groups 5 and 6 |
|---|---|---|---|---|---|
| Age, Continuous | 25.5 years | 25.91 years | 26.14 years | 26 years | 26 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 11 Participants | 4 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 26 Participants | 3 Participants | 9 Participants | 5 Participants |
| Sex: Female, Male Female | 10 Participants | 39 Participants | 7 Participants | 11 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 11 / 11 | 10 / 11 | 7 / 7 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 11 | 0 / 7 |
Outcome results
Primary
Number of Participants With Related Serious Adverse Events
Presence of intervention-related serious adverse events as defined by CTCAE
Time frame: 9 months
Population: Related Serious Adverse Events
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PMED Delivery - Groups 1 and 2 | Number of Participants With Related Serious Adverse Events | 0 Participants |
| IM Injections - Groups 5 and 6 | Number of Participants With Related Serious Adverse Events | 0 Participants |
| Intralesional Delivery - Group 3 and 4 | Number of Participants With Related Serious Adverse Events | 0 Participants |
| Intralesional Delivery + Imiquimod - Group 7 | Number of Participants With Related Serious Adverse Events | 0 Participants |
Secondary
Absence of CIN2/3 Lesion by Week 15
Number of participants with no CIN2/3 lesion at the week 15 visit
Time frame: 15 weeks
Population: Number of participants who had no CIN2/3 at the week 15 resection
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PMED Delivery - Groups 1 and 2 | Absence of CIN2/3 Lesion by Week 15 | 2 Participants |
| IM Injections - Groups 5 and 6 | Absence of CIN2/3 Lesion by Week 15 | 3 Participants |
| Intralesional Delivery - Group 3 and 4 | Absence of CIN2/3 Lesion by Week 15 | 3 Participants |
| Intralesional Delivery + Imiquimod - Group 7 | Absence of CIN2/3 Lesion by Week 15 | 1 Participants |