Clinical trial NCT00788164: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cervical Cancer
Precancerous Condition
HPV Disease
Human Papilomavirus
Keywords: cervical cancer
cervical intraepithelial neoplasia grade 3
therapeutic vaccine
treatment
CIN
HPV
vaccine
Hopkins
Trimble
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-11-10
Enrollment: 75
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Safety and tolerability as determined by number of participants with Serious Adverse Events
timeFrame: 10 weeks from the first intervention
Secondary outcomes:
measure: Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 15
timeFrame: 15 weeks from the date of the first intervention
measure: Change in histology (CIN3 or no CIN3) of biopsies between baseline and week 28
timeFrame: 28 weeks from the date of the first intervention
measure: Quantitative changes in cervical HPV viral load in exfoliated cell samples
timeFrame: 41 weeks from the date of the first intervention
measure: Change in number of lesions by serial digital colposcopy from week 0 to week 15
timeFrame: Change from baseline to 15 weeks
measure: Change in size of lesions by serial digital colposcopy from week 0 to week 15
timeFrame: Change from baseline to 15 weeks
measure: Characterization of peripheral and local tissue response to vaccination
timeFrame: 41 weeks
measure: Correlation of immune response with clinical response
timeFrame: 41 weeks
measure: Correlation between measures of immune response and preclinical experimental data
timeFrame: 41 weeks from the date of the first study intervention
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Cornelia L. Trimble, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maldonado L, Teague JE, Morrow MP, Jotova I, Wu TC, Wang C, Desmarais C, Boyer JD, Tycko B, Robins HS, Clark RA, Trimble CL. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci Transl Med. 2014 Jan 29;6(221):221ra13. doi: 10.1126/scitranslmed.3007323.
citation: Peng S, Ferrall L, Gaillard S, Wang C, Chi WY, Huang CH, Roden RBS, Wu TC, Chang YN, Hung CF. Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody. mBio. 2021 Jan 19;12(1):e03224-20. doi: 10.1128/mBio.03224-20.
citation: Sun YY, Peng S, Han L, Qiu J, Song L, Tsai Y, Yang B, Roden RB, Trimble CL, Hung CF, Wu TC. Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract. Clin Cancer Res. 2016 Feb 1;22(3):657-69. doi: 10.1158/1078-0432.CCR-15-0234. Epub 2015 Sep 29.