* To study the safety of two naked DNA vaccines encoding sig-HELP-kdel and shuffled HPV16 E6 or E7 gene products (sig-HELP-E6SH/E7SH-kdel). * To study the systemic HPV-specific immune response of sig-HELP-E6SH/E7SH-kdel.
ID
Source
Brief title
Condition
- Reproductive neoplasms female benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* To study the systemic HPV-specific immune response of two naked DNA vaccines
encoding sig-HELP-kdel and shuffled HPV16 E6 or E7 gene products
(sig-HELP-E6SH/E7SH-kdel).
Secondary outcome
* To study the safety of sig-HELP-E6SH/E7SH-kdel.
* To study the clinical response to vaccination of sig-HELP-E6SH/E7SH-kdel.
Exploratory objectives:
* To study the migratory capacity of HPV16-specific T cells by analysis of
their presence in vaccine sites.
* The effect of vaccination on the immune infiltrate in VIN lesion
microenvironment will be determined by multicolour fluorescent
immunohistochemistry.
Background summary
Human papilloma virus (HPV) infection is strongly associated with the
development of squamous cell cancer in the
anogenital and head and neck region. HPV16 infection may also cause a chronic
skin disorder of the vulva known as
vulvar intraepithelial neoplasia (VIN). Patients often have a weak or no
spontaneous HPV-specific T cell response which is
thought to be important in the clearance of infection and disease. VIN is a
chronic disease with high relapse rates after
standard treatments. Spontaneous regression are found in 1.2% op patients.
Because the persistence of oncogenic HPV
proteins E6 and E7 is required for carcinogenesis, these viral antigens are
exquisite targets for immunotherapeutic
interventions.
Here we propose to initiate a phase I/II study in patients with HPV16-positive
uVIN lesion using a novel and potent
intradermal HPV DNA vaccination strategy. In preclinical studies this strategy
was shown to be much more potent in the
induction of E6 and E7-specific CD8+ cytotoxic T-cell immunitiy than existing
DNA vaccination strategies, providing a
strong rationale for its clinical evaluation. In this phase I study we will
define the safety, toxicity and immunogenicity of this
highly promising DNA vaccination strategy in patients with a HPV-positive uVIN
lesion. This study will allow us to define
the value of this novel DNA vaccination strategy for the treatment of
HPV-associated (pre)malignancies.
Study objective
* To study the safety of two naked DNA vaccines encoding sig-HELP-kdel and
shuffled HPV16 E6 or E7 gene products (sig-HELP-E6SH/E7SH-kdel).
* To study the systemic HPV-specific immune response of
sig-HELP-E6SH/E7SH-kdel.
Study design
This is a single centre, non-randomized Phase I/II study. Patients with HPV16+
VIN lesions will be enrolled.
The first cohort of patients (n=5) will receive 4 intradermal injections of 2
mg sig-HELP-E6SH/E7SH-kdel on days 0, 14, 28 and 42. Just before
administration, 1 mg of sig-HELP-E6SH-kdel will be mixed with 1 mg of
sig-HELP-E7SH-kdel to have 2 mg of the combined E6SH/E7SH. After all 5 patients
received all vaccination, we will perform an interim analysis by flow
cytometry. There are 2 possible scenarios after the interim analysis:
1. Acceptable immune response
2. Non acceptable immune response
Depending on the outcome of the interim analysis we will continue with the
second cohort of patients.
1. Additional cohort of 9 patients
2. Termination of the trial
Intervention
Sig-HELP-E6SH/E7SH-kdel will be injected intradermally on days 0, 14, 28 and 42
using a permanent make-up device (Derm.MT GmbH, Berlin, Germany).
Study burden and risks
Patients will be vaccinated 4 times with sig-HELP-E6SH/E7SH-kdel using a
permanent make-up device. Further, they will undergo 5
bloodtests, 5 urinetests, 2 times a skin biopsy and twice a biospy of the VIN
lesion. They will come 11 times to the
outpatients clinic for the before mentioned tests and physical examinations.
See appendix I in the protocol for the complete schedule.
The vaccine that is being used in this clinical trial does not contain factors
favoring integration, nor does it contain
sequences that can lead to replication, or that can become part of viruses or
bacteria. Preclinical data show that
intradermal DNA vaccination is much more potent than classical intramuscular
injection. Tattooin of skin is a commonly
used method for treatment of scars or as part of reconstructive surgery.
Tattooing may induce a burning sensation during
tattooing, which will stop the moment the tattooing is ended. Furtermore,
flulike symptoms with fever during 48 hours after
vaccination can occur.
This investigation can lead to a more effective therapy for patients with
HPV-associated (pre)malignincies. There are no
persistent or severe side effects known for this treatment. Therefor we
consider the physical discomfort associated with
participation in this study as acceptable.
NB Update 11-01-2019: No skin biopsies from vaccination site are taken anymore,
due to unability to culture T-cells from the tissue and extra burden for the
patient
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
* Age above 18 years
* Willing and able to undergo the planned study procedures
* Written informed consent
* Histologically proven visible uVIN lesion (histology *3 months prior to enrolment and at least 6 weeks after last treatment)
* HPV16-positive VIN lesion (to be determined on archival tumour tissue (*10 years old); if not available a new biopsy will be required)
* No indication of an active infectious disease: HIV, HCV and HBV negative
* No history of autoimmune disease or systematic undercurrent disease which might affect immunocompetence
* Adequate bone marrow (WBC > 3.0/nL, platelets > 100/nL), renal function (creatinine clearance > 40 mL/min), and liver function (bilirubin < 1.5 x ULN, normal blood coagulation)
Exclusion criteria
* Prior treatment with anti-HPV agents
* Participation in a study with another investigational drug within 30 days prior to enrolment in this study
* Severe cardiac, respiratory, or metabolic disease
* Use of systemic steroids or other immunosuppressive drugs
* Use of oral anticoagulant drugs (except ascal)
* Severe infections requiring antibiotics
* Any treatment for the uVIN lesion within 6 weeks prior to the enrolment (including imiquimod)
* Lactation or pregnancy (if applicable)
* Not willing to take adequate contraceptive measures (if applicable)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005339-42-NL |
| CCMO | NL55908.000.15 |