Therapeutic HPV-16 Vaccination for the Treatment of Anal Dysplasia (VACCAIN-T)

March 13, 2018 updated by: Prof. Jan Prins, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Therapeutic Vaccination Against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men

The objective of the study 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 HPV16-induced intra-anal high-grade AIN (grade 2-3) that failed on, or recurred after previous treatment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Rationale: Since the introduction of combination antiretroviral therapy (cART), human immunodeficiency virus (HIV)-related morbidity and mortality have considerably decreased. However, as a result of the significantly prolonged life span of HIV-positive patients, new causes of morbidity and mortality have become evident. In particular, anal cancer incidence has increased dramatically in HIV-positive men. Like cervical cancer, anal cancer is causally linked to infections with high-risk papillomaviruses (HPV), and is preceded by cancer precursor lesions: anal intraepithelial neoplasia (AIN). Over 90% of HIV-positive MSM have persisting anal HPV infection, in 88% of patients high-risk HPV is present, and high-grade disease (AIN 2 or 3, HG AIN) is present in 25-52% of all HIV+ MSM. The majority of HG AIN is caused by HPV type 16. As in cervical intraepithelial neoplasia, early diagnosis and treatment of AIN have been advocated to prevent malignancy.

Several treatment options exist for AIN, but success rates are disappointingly low. An alternative strategy might be therapeutic HPV vaccination. In women with vulvar intraepithelial neoplasia (VIN), a condition with a comparable pathogenesis, therapeutic vaccination with a synthetic long-peptide vaccine SLP-HPV-01® , consisting of a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7, was well tolerated, and proved to be effective in a high percentage of women, with a durable response, and induction of HPV-16-specific immunity.

Objective: 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.

Study population: HIV-positive MSM 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.

During the past years the study group in the Academic Medical Center in Amsterdam has built a large cohort of well-characterized HIV-positive patients with histology-proven AIN. Material has been stored of these patients and their lesions. Those patients with AIN resistant to previous treatment will be identified. The causative HPV type will be determined in stored biopsies of these patients, using microdissection (LCM) and in-situ PCR. Only patients with HPV-16-induced lesions (the majority of patients) will be eligible for the current study.

Study design: : The first phase of the study is a dose-response study, with four different dosage schedules (1,5,10; 5,10,20; 10,20,40 and 40,40,40,40 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.

Intervention: Patients will be vaccinated 3 or 4 times with a 3-week interval with the SLP-HPV-01® vaccine.

High-resolution anoscopy (HRA) will be performed at inclusion, and repeated at 3, 6,12 and 18 months. The transformation zone will be photographed at each visit. Detailed photos plus biopsies of lesion sites will be obtained. From venous blood samples PBMCs will be obtained before the first (pre), 3 weeks after the first vaccination (post-1), 3 weeks after the second vaccination (post-2), 3 weeks after the third vaccination (post-3) and if applicable 3 weeks after the fourth vaccination (post-4).

Endpoints: 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, 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
        • Academic Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Written informed consent
  • Age ≥ 18 years
  • HIV+ MSM, CD4 count > 350/ul (maximum 3 months before screening visit)
  • Biopsy-proven intra-anal high-grade AIN caused by HPV16, resistant to, or recurring after previous treatment with cauterization (or other local treatment), 5FU or imiquimod. A patient is considered resistant to cauterization if after 2 cauterization sessions still lesions are found. A patient is considered resistant to 5FU or imiquimod if after 4 months of weekly (multiple day) application still lesions are found.
  • Good performance status (a Karnofsky performance score of ≥60 [on a scale of 0 to 100, with higher scores indicating better performance status])
  • Normal pretreatment laboratory blood values as described previously. This means: Leukocytes >3 x 109/L, lymfocytes >1 x 109/L, trombocytes >100 x 109/L and hematocrit >30%.

Exclusion Criteria:

  • Immunosuppressive medication or other diseases associated with immunodeficiency
  • Life expectancy < 1 year
  • History of anal carcinoma
  • IFN-α criteria (see SmPC): severe cardiac, thyroid, hepatic or central nervous system disease, including severe depression in the past.
  • Previous HPV vaccination
  • Currently treated with IFN-α against hepatitis C

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: HPV-16 vaccine
Drug: HPV-16 vaccine
Vaccination with SLP-HPV-01® with or without interferon-a injections.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Safety/ toxicity of the HPV-16 vaccine in HIV+ MSM
Time Frame: up to 18 months
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.
up to 18 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Regression of intra-anal high grade AIN lesion
Time Frame: Primary outcome: 3, 6, 12 months. Secondary: 18 months.
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.
Primary outcome: 3, 6, 12 months. Secondary: 18 months.

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
HPV16-specific immunity in blood
Time Frame: 3 weeks after the 1st, 2nd and 3rd vaccination

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.
3 weeks after the 1st, 2nd and 3rd vaccination
Regression of peri-anal high grade AIN lesions
Time Frame: 3, 6, 12 and 18 months
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.
3, 6, 12 and 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Leiden University Medical Center
ISA Pharmaceuticals B.V.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 6, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 13, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 15, 2013

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 15, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 13, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL42802.000.12

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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