Vaccine Therapy With or Without Imiquimod in Treating Patients With Grade 3 Cervical Intraepithelial Neoplasia

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Cervical Cancer, Precancerous Condition, HPV Disease, Human Papilomavirus

Intervention / Treatment
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* Biological: TA-HPV
* Biological: pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine
* Drug: imiquimod


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Groups 1-3<br>Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine intramuscularly (IM) on days 1 and 29 and TA-HPV vaccine IM on day 57. | Biological: TA-HPV<br>* Given intramuscularly<br>Biological: pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine<br>* Given intramuscularly<br>|
| Experimental: Group 4<br>Patients receive topical imiquimod on days 1, 29, and 57. | Drug: imiquimod<br>* Given topically<br>|
| Experimental: Group 5<br>Patients receive pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine and TA-HPV vaccine as in groups 1-3, and imiquimod as in group 4. | Biological: TA-HPV<br>* Given intramuscularly<br>Biological: pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine<br>* Given intramuscularly<br>Drug: imiquimod<br>* Given topically<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as determined by number of participants with Serious Adverse Events | Presence of Serious Adverse Events (as defined by according to NCI CTCAE v3.0) or dose limiting toxicities related to the study drugs. | 10 weeks from the first intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 15 | Absence of CIN3 as assessed by colposcopically directed biopsy at week 15 | 15 weeks from the date of the first intervention | 
| Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 28 | Absence of CIN3 as assessed by colposcopically directed biopsy at week 28. | 28 weeks from the date of the first intervention | 
| Quantitative changes in cervical HPV viral load in exfoliated cell samples | HPV genotypes present at study entry which become undetectable during the study window | 41 weeks from the date of the first intervention | 
| Change in number of lesions by serial digital colposcopy from week 0 to week 15 | Number of lesions that were present at baseline, then become undetectable by colposcopy at week 15 | Change from baseline to 15 weeks | 
| Change in size of lesions by serial digital colposcopy from week 0 to week 15 | Change in size of lesions from baseline to week 15. | Change from baseline to 15 weeks | 
| Characterization of peripheral and local tissue response to vaccination | 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 | 41 weeks | 
| Correlation of immune response with clinical response | Compare immune responses in the blood with histologic regression of CIN3 to CIN1 or less | 41 weeks | 
| Correlation between measures of immune response and preclinical experimental data | Compare immune responses detected in patients who received the study intervention to those detected in the preclinical animal model. | 41 weeks from the date of the first study intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cervical cancer, cervical intraepithelial neoplasia grade 3, therapeutic vaccine, treatment, CIN, HPV, vaccine, Hopkins, Trimble