Primary objective: * Examine the safety and tolerability, both local and general, of ProCervix Solution (escalating doses) and ProCervix Powder in women infected by HPV 16 and/or 18 with normal cytology from Week 0 to Week 10. Secondary objectives…
ID
Source
Brief title
Condition
- Viral infectious disorders
- Female reproductive tract infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
- treatment-emergent adverse events (AEs) including serious adverse events
(SAEs)
- treatment-emergent changes in clinical laboratory tests,
- vital signs
- physical examinations
- exams directed at the vaccination site
- observations on the status of HPV 16 and HPV 18 infection
- cytology in cervical scrapings from before and after exposure to ProCervix
Immunogenicity:
- tests of humoral immunity to HPV
- test of cellular immunity to HPV
- assessment of cellular immune response (changes in peripheral blood [PB]
T-cell responses to the E7 antigen of HPV 16 and HPV 18)
- evaluation of serologic response (changes in anti-HPV 16 E7 and anti-HPV 18
E7 antibody titres)
Secondary outcome
Immunological assessments other than the antigen specific measures listed above
will be evaluated in subjects using available material from preserved
peripheral blood mononuclear cells, plasma and cervical samples, to
characterize immunological responses to ProCervix.
Background summary
Cervical cancer is the second most common malignancy among women worldwide,
with approximately 500,000 new cases diagnosed each year, and about 275,000
deaths per year.
Human Papillomavirus (HPV) infection with certain high risk subtypes is a
prerequisite for the development of cervical cancer and HPV is detected in
99.7% of cervical carcinomas. Human Papillomavirus 16 and HPV 18 (the two
genotypes targeted by the ProCervix vaccine) are the most common genotypes
associated with cervical cancer. They are present as either single or multiple
infections in at least 70% of squamous cell carcinoma and 84% of
adenocarcinomas of the cervix.
It is thought that the integration of HPV DNA into the human genome is an
important (but not essential) step for persistent transcription of E6 and E7
genes. These oncogenes disrupt normal cell cycle control mechanisms and cause
malignant transformation of epithelial cells by inactivation of P53 by E6
protein and/or inactivation of Rb by the E7 protein. Human Papillomavirus 16
and/or HPV 18 infections are more persistent than infections with other
genotypes and 50% are still present 12-18 months after detection.
ProCervix is based on a novel potent Ag delivery system: the recombinant
adenylate cyclase (CyaA) vector based on the detoxified adenylate cyclase of
Bordetella pertussis.
The Investigational Product (IP) consists of two recombinant CyaA proteins,
CyaA-HPV16E7 (C16-1) and CyaA-HPV18E7 (C18 1) in a 50/50 ratio (C16C18-1
antigen [Ag] mixture). The HPV E7 protein was chosen as the Ag for these two
HPV subtypes because it is a small, well conserved protein with T-helper and
cytotoxic T lymphocyte (CTL) epitopes for the most common types of human
lymphocyte antigen (HLA). Cellular immunity to HPV-16 E7 has been shown to be
associated with clinical and cytological resolution of HPV-induced CIN or
vulval intraepithelial neoplasia (VIN), indicating that E7-specific T-cells
have a role in the control of HPV disease.
ProCervix is adjuvanted by Aldara*, a cream containing 5% of Imiquimod and
approved in the EU and the US for topical treatment of various skin conditions.
Functional studies of ProCervix and Aldara* in the TC-1 E7 expressing tumour
mouse model support the use of this cream as the ProCervix adjuvant
Study objective
Primary objective:
* Examine the safety and tolerability, both local and general, of ProCervix
Solution (escalating doses) and ProCervix Powder in women infected by HPV 16
and/or 18 with normal cytology from Week 0 to Week 10.
Secondary objectives:
* Examine the safety and tolerability, both local and general, of ProCervix
Solution (escalating doses) and ProCervix Powder in women infected by HPV 16
and/or 18 with normal cytology from Week 10 to Week 26.
* Examine the cellular and humoral immunogenicity of ProCervix in women
infected by HPV 16 and/or 18 with normal cytology from Week 0 to Week 26.
Study design
This is a phase I, single-centre, open-label (Cohorts 1 and 2), multicentre,
randomized, double-blinded, placebo-controlled (Cohort 3), and multicentre,
open-label (Cohort 4) study of the safety, tolerability, and immunogenicity of
escalating paired doses of ProCervix followed by Imiquimod as a vaccine
adjuvant in healthy adult female subjects infected by HPV 16 and/or 18 with
normal cervical cytology.
Cohort 1 and 2 interventions have been completed in Belgium and are not
applicable to Dutch subjects.
Subjects in Cohorts 3 will be treated with ProCervix in a solution formulation,
or placebo;
subjects in Cohort 4 will be treated with ProCervix in a freeze-dried (powder)
formulation.
Intervention
Cohort 1
* 100 mcg ProCervix (solution) on day 1 and day 42 and Imiquimod on day 1,2, 42
and 43.
Cohort 2
* 600 mcg ProCervix (solution) on day 1 and day 42 and Imiquimod on day 1,2, 42
and 43.
Cohort 3
* 600 mcg ProCervix (solution) on day 1 and day 42 and Imiquimod on day 1,2, 42
and 43 or,
* 600 mcg ProCervix (solution) on day 1 and day 42 and Imiquimod on day 1,2, 42
and 43 or
* Placebo injections on day 1 and 42 and Imiquimod on day 1,2, 42 and 43.
Cohort 4
* 600 mcg ProCervix (powder) on day 1 and day 42 and Imiquimod on dag 1,2, 42
and 43.
Cohort 1 en 2 have been performed in Belgium.
Cohort 3 is being performed in Belgium (recruitment completed).
Cohort 4 will take place in Belgium and the Netherlands (VUmc).
Study burden and risks
The intended effect of vaccination with ProCervix is the prevention of
progression from cervical infection with papillomavirus (serotype 16 and or 18)
to high grade neoplastic lesions and cervical carcinoma. Although the trial
population in study PC10VAC01 consists of women at risk because of infection
with the relevant strain(s) of Human Papillomavirus, no direct (cancer or
cytologically based) or indirect (immunologic) evaluations of the efficacy of
human exposure to ProCervix are presently available. The benefits of exposure
to ProCervix plus Imiquimod in PC10VAC01 include the altruistic benefit of
contributing to research related to the treatment of a life-threatening illness
and the unproved possibility of decreasing the chance of development of
HPV-related high grade neoplastic lesions and cervical cancer. As noted in the
Investigational Medicinal Product Dossier (IMPD) and the DSUR, the observed
risks of exposure to ProCervix plus Imiquimod have been limited to effects,
primarily local, that were anticipated from prior pre-clinical and clinical
experience. The safety experience of subjects in PC10VAC01 has been reviewed
formally on seven occasions by the investigators and other members of the SRC.
On each occasion, the reviewers have examined the available safety data with
particular attention to the grade 2 and 3 local effects observed after exposure
to study vaccine and study cream. On each occasion, the SRC has approved
continuation of the trial, indicating support for the potential benefit of
ProCervix as an effect that would outweigh the side effects observed in the
trial to date.
28, Rue du Dr. Roux
75724 PARIS Cedex 15
FR
28, Rue du Dr. Roux
75724 PARIS Cedex 15
FR
Listed location countries
Age
Inclusion criteria
1. Female between the ages of 18 and 45 years (inclusive), in general good health with HPV infection confirmed by 2 genotyping tests showing one or both type 16 and type 18.
2. Subject has two consecutive normal cervical cytological evaluations, separated by 6 weeks to 12 months prior to enrolment.
3. Subject has a normal gynaecologic examination.
4. Subject has employed highly effective contraception for the month prior to the first vaccination and will agree to employ highly effective contraception for at least 4 months after the last vaccination.
5. Subject has a CD4+ total count *500cells/mm3.
6. Subject is in general good health based on medical history and clinically acceptable results, in the judgment of the Investigator, on the following assessments: physical examination, vital signs, clinical chemistry, and haematology.
Exclusion criteria
1. Subject has a current acute or chronic disease, other than infection with HPV that would increase the expected risk of exposure to ProCervix or Imiquimod or would be expected to interfere with the planned evaluations of response to ProCervix, in the judgment of the Investigator.
2. Subject has prior exposure to HPV prophylactic vaccine.
3. Subject has a history of cancer of the cervix or of untreated high grade abnormal cervical cytological evaluation.
4. Subject has received any prophylactic or therapeutic vaccine within 4 weeks of first vaccination.
5. Subject has current systemic infection or any history of primary or secondary systemic immunosuppression.
6. Subject has a history of severe allergy (requiring hospital care) or history of asthma requiring drug management in the last year.
7. Subject has a history of malignancy.
8. Subject was dosed with another investigational drug within 30 days prior to the Screening Visit.
9. Subject has a known history of hypersensitivity to Imiquimod.
10. Subject has a history of severe reaction to any drug or prior vaccination.
11. Subject has a medical condition with clinical and/or biological consequences judged by the investigator incompatible with vaccination(s).
12. Subject is known to have current infection with any other sexually transmitted infection.
13. Subject has a symptomatic vaginal or genital infection.
14. Subject is pregnant or is nursing.
15. Subject has participated in the past in another clinical trial of vaccination related to infection with HPV.
16. Subject has donated blood or plasma within 60 days prior to the Screening Visit.
17. Subject has a prior exposure to ProCervix.
18. Women negative for one or both HPV genotyping tests.
Design
Recruitment
Medical products/devices used
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 | EUCTR2010-018629-21-NL |
| CCMO | NL37216.000.11 |