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…
ID
Source
Brief title
Condition
- Viral infectious disorders
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 the lesion sites.
Secondary outcome
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.
Background summary
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.
Study 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 design
The first phase of the study is a dose-response study, with 4 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 (post-1), 3 weeks after the second vaccination (post-2), 3
weeks after the third vaccination (post-3) as well as 3 weeks after the 4th
vaccination (post-4).
Study burden and risks
During the course of the study high-resolution anoscopy (HRA) will be performed
five times, in total 545 ml blood will be drawn, and the patient has to visit
the AMC in total 12 times during the 18 months of the study. Potential risks
are the possible side effects of the vaccine and the Pegintron injections.
This is justified by the fact that the vaccine was tolerated well during a
previous study in women with vulvar neoplasia, and therapy is intended to be
therapeutic for their therapy-resistant high-grade anal intra-epithelial
neoplasia, which is a very prevalent condition among HIV+ men who have sex with
men.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
• HIV+, CD4 count > 350/ul,
• Biopsy-proven intra-anal high-grade AIN caused by HPV16, resistant to, or recurring after previous treatment with cauterization, 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
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.
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 | EUCTR2012-005466-34-NL |
| CCMO | NL42802.000.12 |