Description:
RATIONALE: Vaccines made from DNA or a gene-modified virus may help the body build an
effective immune response to kill tumor cells. Biological therapies, such as imiquimod, may
stimulate the immune system in different ways and stop tumor cells from growing. Applying
topical imiquimod to the cervix may be an effective treatment for cervical intraepithelial
neoplasia. Giving vaccine therapy together with imiquimod may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of vaccine therapy and
to see how well it works when given with or without imiquimod in treating patients with grade
3 cervical intraepithelial neoplasia.
Title
- Brief Title: Vaccine Therapy With or Without Imiquimod in Treating Patients With Grade 3 Cervical Intraepithelial Neoplasia
- Official Title: A Phase I Efficacy and Safety Study of HPV16-specific Therapeutic DNA-vaccinia Vaccination in Combination With Topical Imiquimod, in Patients With HPV16+ High Grade Cervical Dysplasia (CIN3)
Clinical Trial IDs
- ORG STUDY ID:
J0656
- SECONDARY ID:
NA_00002176
- SECONDARY ID:
CDR0000617261
- SECONDARY ID:
2P50CA098252
- SECONDARY ID:
1R21CA123876
- NCT ID:
NCT00788164
Conditions
- Cervical Cancer
- Precancerous Condition
- HPV Disease
- Human Papilomavirus
Interventions
| Drug | Synonyms | Arms |
|---|
| TA-HPV | | Group 5 |
| pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine | | Group 5 |
| imiquimod | | Group 4 |
Purpose
RATIONALE: Vaccines made from DNA or a gene-modified virus may help the body build an
effective immune response to kill tumor cells. Biological therapies, such as imiquimod, may
stimulate the immune system in different ways and stop tumor cells from growing. Applying
topical imiquimod to the cervix may be an effective treatment for cervical intraepithelial
neoplasia. Giving vaccine therapy together with imiquimod may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of vaccine therapy and
to see how well it works when given with or without imiquimod in treating patients with grade
3 cervical intraepithelial neoplasia.
Detailed Description
OBJECTIVES:
Primary
- To evaluate safety, tolerability, and feasibility of pNGVL4a-Sig/E7(detox)/HSP70 DNA
vaccine and TA-HPV vaccine with or without imiquimod in patients with human
papillomavirus (HPV)16-positive grade 3 cervical intraepithelial neoplasia (CIN3).
Secondary
- To evaluate the effect of this regimen on histology, based on the regression of cervical
intraepithelial neoplasia.
- To evaluate the feasibility and safety of study immunotherapy in these patients.
- To evaluate the quantitative changes in cervical HPV viral load in these patients
following study immunotherapy.
- To evaluate changes in lesion size.
- To evaluate the cellular and 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.
- To evaluate if the efficacy of the prime-boost vaccination can be improved with the
cervical application of imiquimod.
OUTLINE: This is a dose escalation study of TA-HPV vaccine (groups 1-3 only). Patients are
assigned to 1 of 5 treatment groups.
- Groups 1-3: Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine intramuscularly
(IM) in weeks 0 and 4 and TA-HPV vaccine IM in week 8.
- Group 4: Patients receive topical imiquimod applied to the cervix once in weeks 0, 4,
and 8.
- Group 5: Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine and TA-HPV vaccine as
in groups 1-3, and imiquimod as in group 4.
Patients experiencing no improvement of their lesions at week 15 undergo standard cone
resection of the squamocolumnar junction. If there is either 1) regression of the size of the
lesions by colposcopy and/or 2) no CIN3 lesions detected by colposcopy/biopsy and Pap smear
and/or 3) significant decrease of HPV viral load, patients are followed until week 28. At
that time, loop electrosurgical excision procedure (LEEP) resection is performed if there is
a CIN3 lesion detected by colposcopy/biopsy or suspected by Pap smear. Patients undergoing
LEEP are followed until week 32. Patients not undergoing LEEP are followed until week 41 to
confirm CIN3 regression.
Blood and tissue samples are collected periodically to measure immune response via ELISA,
determine viral load and identify co-infecting HPV types via reverse-line blotting, and
analyze lymphocytes via flow cytometry.
PROJECTED ACCRUAL: A total of 36 patients (3 in groups 1 and 2, 12 in groups 3 and 5, and 6
in group 4) will be accrued for this study.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Groups 1-3 | Experimental | Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine intramuscularly (IM) on days 1 and 29 and TA-HPV vaccine IM on day 57. | - TA-HPV
- pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine
|
| Group 4 | Experimental | Patients receive topical imiquimod on days 1, 29, and 57. | |
| Group 5 | Experimental | Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine and TA-HPV vaccine as in groups 1-3, and imiquimod as in group 4. | - TA-HPV
- pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine
- imiquimod
|
Eligibility Criteria
DISEASE CHARACTERISTICS:
- Colposcopically and biopsy confirmed grade 3 cervical intraepithelial neoplasia
- Human papillomavirus (HPV) 16-positive disease by PCR
- Measurable disease after diagnostic biopsy
- No concurrent adenocarcinoma in situ of the cervix
PATIENT CHARACTERISTICS:
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use an effective form of contraception during study treatment
- Immunocompetent
- No concurrent malignancy, except for nonmelanoma skin lesions
- No serious concurrent disorder, including any of the following:
- Active systemic infection
- Autoimmune disease
- Proven or suspected immunosuppressive disorder
- Major medical illnesses of the cardiovascular or respiratory system
- No evidence or history of cardiac disease, including any of the following:
- Congestive heart failure
- Symptomatic arrhythmia not controlled by medication
- Unstable angina
- History of acute myocardial infarction or cerebrovascular accident within the
past 6 months
- No history of severe allergy including eczema or other exfoliative skin disorder
- No active eczema within the past 12 months
- No concurrent skin conditions, including any of the following:
- Burns
- Traumatic or pruritic skin conditions
- Open wounds
- Unhealed surgical scars
- Patients and their close social, sexual, or domestic contacts may not have any of the
following active skin diseases:
- Psoriasis
- Lichen planus
- Sever acneiform rash
- Impetigo
- Varicella zoster
- Sepsis
- No close social contact with children under 5 years old
- No close social or domestic contact with a pregnant woman
- No HIV seropositivity
- No allergy to eggs
PRIOR CONCURRENT THERAPY:
- No previous vaccination with vaccinia
- No immunosuppressive medication (i.e., steroid therapy or other
immunosuppressive/immunomodulating drugs [e.g., cyclosporine]) within the past 2
months
- No investigational agent(s) within the past 6 months
- No concurrent participation in another experimental protocol
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Safety and tolerability as determined by number of participants with Serious Adverse Events |
| Time Frame: | 10 weeks from the first intervention |
| Safety Issue: | |
| Description: | Presence of Serious Adverse Events (as defined by according to NCI CTCAE v3.0) or dose limiting toxicities related to the study drugs. |
Secondary Outcome Measures
| Measure: | Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 15 |
| Time Frame: | 15 weeks from the date of the first intervention |
| Safety Issue: | |
| Description: | Absence of CIN3 as assessed by colposcopically directed biopsy at week 15 |
| Measure: | Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 28 |
| Time Frame: | 28 weeks from the date of the first intervention |
| Safety Issue: | |
| Description: | Absence of CIN3 as assessed by colposcopically directed biopsy at week 28. |
| Measure: | Quantitative changes in cervical HPV viral load in exfoliated cell samples |
| Time Frame: | 41 weeks from the date of the first intervention |
| Safety Issue: | |
| Description: | HPV genotypes present at study entry which become undetectable during the study window |
| Measure: | Change in number of lesions by serial digital colposcopy from week 0 to week 15 |
| Time Frame: | Change from baseline to 15 weeks |
| Safety Issue: | |
| Description: | Number of lesions that were present at baseline, then become undetectable by colposcopy at week 15 |
| Measure: | Change in size of lesions by serial digital colposcopy from week 0 to week 15 |
| Time Frame: | Change from baseline to 15 weeks |
| Safety Issue: | |
| Description: | Change in size of lesions from baseline to week 15. |
| Measure: | Characterization of peripheral and local tissue response to vaccination |
| Time Frame: | 41 weeks |
| Safety Issue: | |
| Description: | Compare immune responses in the blood to local immune responses in the tissue for patients who receive the study intervention, from serially obtained peripheral blood specimens and on tissue samples from therapeutic resection |
| Measure: | Correlation of immune response with clinical response |
| Time Frame: | 41 weeks |
| Safety Issue: | |
| Description: | Compare immune responses in the blood with histologic regression of CIN3 to CIN1 or less |
| Measure: | Correlation between measures of immune response and preclinical experimental data |
| Time Frame: | 41 weeks from the date of the first study intervention |
| Safety Issue: | |
| Description: | Compare immune responses detected in patients who received the study intervention to those detected in the preclinical animal model. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
Trial Keywords
- cervical cancer
- cervical intraepithelial neoplasia grade 3
- therapeutic vaccine
- treatment
- CIN
- HPV
- vaccine
- Hopkins
- Trimble
Last Updated
June 12, 2020
