This study aims to validate the potential of immune related biomarkers to predict the clinical response of patients with primary cHSIL to imiquimod and aims to explore the value of these immune biomarkers in recurrent/residual cHSIL to predict…
ID
Source
Brief title
Condition
- Cervix disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Confirm the relationship between a complete clinical response to imiquimod
and the increased stromal infiltration of CD4+ T cells, CD11c+ cells and/or
M1-like macrophages as well as the decreased infiltration with FoxP3+ Tregs in
primary cHSIL.
• Validate the association of a *hot signature*, defined as the sum of the
numbers of stromal CD4+/CD11c+/M1+ cells per square millimeter minus the number
of stromal FoxP3+ cells per square millimeter, with a complete response to
imiquimod treatment in primary cHSIL.
• Determine the sensitivity and specificity of the *hot signature* in patients
with primary cHSIL lesions to estimate the predictive value for therapy
efficacy upon imiquimod treatment.
Secondary outcome
• Explore the *hot signature* as a predictive biomarker for therapy efficacy to
imiquimod treatment in patients with residual/recurrent cHSIL (rrcHSIL).
• Explore the *hot signature* as a predictive biomarker for spontaneous
regression of cHSIL (e.g. CIN2).
• Determine treatment efficacy, HPV clearance, therapy adherence and reported
side effects upon imiquimod therapy.
• Evaluate maintenance of lesion regression after imiquimod treatment by
determination of recurrent cHSIL or progression to cervical cancer and time to
recurrence/progression.
• Explore and evaluate other potential more specific predictive (immune)
biomarkers in cHSIL which are easily accessible and readily implemented for
clinical prognosis, including dedicated gene expression profiles by Nanostring
and gene methylation assays.
• Develop a simplified pathological scoring system by explorative development
of a simplified dual immunohistochemistry protocol to identify the hot
signature and exploration of the predictive value of this *immunoscore* in
cHSIL.
• Validate the *hot signature* defined as epithelial or stromal
CD4+/CD11c+/CD68+ cells via single immunohistochemistry per square millimeter
with a complete response to imiquimod treatment in primary cHSIL
• Determine the vaginal microbiome in cHSIL patients treated with imiquimod or
not treated to explore the potential interaction of the vaginal microbiome and
composition of immune infiltrates and the relation to imiquimod treatment and
relation to spontaneous regression.
Background summary
A persistent high risk Human Papilloma Virus (hrHPV) infection can cause
(pre)malignant anogenital lesions of the cervix, vulva or vagina. Cervical high
grade squamous intraepithelial lesions (cHSIL) have a malignant potential and
require adequate therapy. The natural history of cHSIL is unpredictable: ~25%
of cHSIL will regress, while 18% will progress to invasive cervical cancer. The
standard treatment of histologically confirmed cHSIL is surgical excision by
large loop excision of the transformation zone (LLETZ), with potential
complications, such as hemorrhage, infection and an increased risk of preterm
birth in subsequent pregnancies. Imiquimod cream has been studied as a
non-invasive treatment alternative and in our recent TOPIC-3 study for cHSIL we
report a complete response rate of 55% upon imiquimod therapy. Imiquimod is now
considered as a standard non-surgical therapy for patients with cHSIL in the
Netherlands, especially in those patients with a future pregnancy wish.
Side-effects of imiquimod therapy however are common and can be extensive,
consisting mostly of local inflammation and burning, but also systemic adverse
events such as headache and flu-like symptoms. Therapy adherence is challenging
with up to 20% discontinuation of treatment due to the side effects and the 16
week treatment duration. As such, biomarkers which can predict response to
imiquimod therapy are warranted, to increase therapy efficacy and to avoid side
effects in patients who will not respond. Our previous work shows that clinical
response to imiquimod in cHSIL is associated with a coordinated pre-existing
type 1 T cell- and inflammatory myeloid cell infiltration and provided the
first set of parameters that potentially can function together as a predictive
biomarker CIBI (CHSIL Immune Biomarker for Imiquimod (CIBI)).
Study objective
This study aims to validate the potential of immune related biomarkers to
predict the clinical response of patients with primary cHSIL to imiquimod and
aims to explore the value of these immune biomarkers in recurrent/residual
cHSIL to predict treatment responses for imiquimod and aims to explore theit*s
potential in spontaneous regression of cHSIL (CIN2).
Study design
Multicenter, real-life prospective cohort validation study.
Study burden and risks
The burden associated with participation to this study is minimal since
patients are included in accordance to real-life selection. If patients prefer
imiquimod treatment for the therapy for their cHSIL lesion after consultation
with the gynecologist they will be treated following a standard protocol,
following the national guideline for cHSIL (CIN, AIS en VAIN.pdf). The burden
for patients to participate in the study lies in an extra biopsy taken at
colposcopy at 20 weeks and taking vaginal cultures for microbiome analysis. The
benefit for the patients lies in extra support via telephonic consultation and
close monitoring. For the patients in the observational arm with no treatment,
no extra examinations will be performed according to the national guideline for
cHSIL, only data and tissue will be used and two vaginal swabs taken. For the
study cohort the benefit is limited but if we are able to identify a clinical
predictive biomarker for spontaneous regression or imiquimod in cHSIL, this may
increase therapy efficacy for future cHSIL patients by patient selection
preventing unnecessary (imiquimod) therapy.
Michelangelolaan 2
Eindhoven 5623 EJ
NL
Michelangelolaan 2
Eindhoven 5623 EJ
NL
Listed location countries
Age
Inclusion criteria
- Primary cHSIL lesions (e.g. CIN3 or CIN 2), histologically confirmed by
diagnostic biopsy
NB: In case of CIN 2, <30 years, expectative management must be discussed
according to the Dutch national guideline with the patient, if the patient
prefers imiquimod therapy the patient can be treated with imiquimod and
enrolled in the study, if the patient prefers expectative management they can
be enrolled in the observational CIN 2 arm.
- Recurrent or residual cHSIL lesions after initial LLETZ treatment (e.g. CIN2
or CIN3), histologically confirmed by diagnostic biopsy
- Age of 18 years or older
Exclusion criteria
- Concomitant diagnoses of VAIN (vaginal intraepithelial neoplasia e.g. vaginal
HSIL)
- PAP 4 cytology as indication for the baseline colposcopy at study entrance
- Adenocarcinoma in situ (AIS) diagnosis
- Previous imiquimod therapy for cHSIL
- previous cervical malignancy
- current malignant disease
- immunodeficiency (including HIV/AIDS and immunosuppressive medication)
- pregnancy
- legal incapability
- insufficient knowledge of the Dutch language
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 |
|---|---|
| CCMO | NL79879.100.22 |