Therapeutic HPV-16 Vaccination for the Treatment of Anal Dysplasia (VACCAIN-T)
Anal cancer incidence has increased dramatically in HIV (human immunodeficiency virus)-positive men. Like cervical cancer, anal cancer is causally linked to infections with high-risk papillomaviruses, and is preceded by precursor lesions: anal intraepithelial neoplasia (AIN). Several treatment options exist for AIN, but success rates are disappointingly low. An alternative strategy might be therapeutic HPV (human papilloma virus) vaccination. In women with vulvar intraepithelial neoplasia (VIN), a condition with a comparable pathogenesis, therapeutic vaccination with HPV-16 viral oncoproteins E6 and E7, was well tolerated, and proved to be effective.
The objective of the current proposal is to assess, in a phase 1/2 study, the safety and efficacy of this synthetic vaccine SLP-HPV-01® in HIV+ men with CD4 counts > 350 x 10E6/l and intra-anal high-grade, HPV16 positive AIN, who failed on previous treatment.
HIV-positive MSM (men who have sex with men) with a CD4 count > 350 cells/ul with HPV16-induced intra-anal high-grade AIN (grade 2-3) that was resistant to, or recurred after conventional cauterization or other forms of local treatment.
The first phase of the study is a dose-response study, with 3 different dosage schedules (1,5,10; 5,10,20; and 10,20,40 μg of SLP-HPV-01®, administered intradermally with a three-week interval), each dosage schedule with or without the co-administration of pegylated interferon-α (Pegintron 1 μg/kg s.c.) at the day of vaccine administration. Each vaccination schedule is to be tested in 5 patients.
The vaccination schedule that induces in HIV-positive MSM the best HPV16-specific response compared to that of the women with VIN in our previous study, is considered the optimal schedule. The size of this dose group will be increased to a total of 20 patients by treating an additional 15 patients.
Patients will be vaccinated 3 times with a 3-week interval with the SLP-HPV-01® vaccine.
The primary clinical end points will be both toxicity/ safety, and the regression of the lesions at 3, 6 and 12 months, as assessed by HRA (high resolutions anoscopy), with biopsies taken of lesion sites.
Secondary endpoints are regression of lesions at 18 months and HPV16-specific immunity in blood will be measured: i.e. ELISPOT (IFNg) for ex-vivo detection of antigen-specific responses and multiparametric intracellular cytokine/extracellular activation marker staining to determine the type (CD4+ and/or CD8+) and function (activation status and/or cytokines) of T-cells that respond.
Anal Intraepithelial Neoplasia
Drug: HPV-16 vaccine
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Therapeutic Vaccination Against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men|
- Safety of the HPV-16 vaccine in HIV+ MSM [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]Monitoring for spontaneous adverse events and injection-site reactions will be done weekly for three weeks after each vaccination. Clinical assessments and laboratory tests (routine hematology and chemistry) will be performed before the second and third vaccination and thereafter every 3 months for a total of 18 months of follow-up. Adverse events are graded according to version 3.0 of the Common Terminology Criteria for Adverse Events (CTCAE), which grades events on a scale of 1 to 5, with higher grades indicating greater severity.
- Regression of the AIN lesion [ Time Frame: 18 months ] [ Designated as safety issue: No ]High resolution anoscopy is performed to monitor the AIN lesions. Biopsies will be obtained of suspected lesions. Complete response is defined as histological resolution of AIN, partial response is defined as regression from high grade to low grade AIN. In case of persisting high grade AIN, a partial response is defined as a decrease in lesion size of 50% or more.
- HPV16-specific immunity in blood [ Time Frame: 3 weeks after last vaccination ] [ Designated as safety issue: No ]
In order to assess the systemic changes in immunity, which are induced by vaccination we will examine venous blood samples by using peripheral blood lymphocytes that are tested by a set of complementary T-cell assays: i.e. proliferation (LST), cytokine production (IFNg, TNFa, IL-4, IL-5, IL-10, and IL-2) as well as by ELISPOT (IFNg) for ex-vivo detection of antigen-specific responses and by multiparametric intracellular cytokine/extracellular activation marker staining to determine the type (CD4+ and/or CD8+) and function of T-cells that respond.
A vaccine-induced response is defined as a 3-fold increase compared to the pre-vaccination result.
|Study Start Date:||August 2013|
|Estimated Study Completion Date:||August 2016|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
|Experimental: HPV-16 vaccine||
Drug: HPV-16 vaccine
Vaccination with SLP-HPV-01® with or without interferon-a injections.
|Contact: Karien C Gosens, MDemail@example.com|
|Contact: Jan M Prins, prof, MDfirstname.lastname@example.org|
|Academic Medical Center|
|Amsterdam, Noord-Holland, Netherlands, 1105 AZ|
|Principal Investigator:||Jan M Prins, professor||Academic Medical Center, Amsterdam|