Brief Title
Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment
Official Title
Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment
Brief Summary
Imiquimod is a good non-invasive treatment option for women with cervical high-grade squamous
intraepithelial neoplasia (cHSIL), especially those with a possible (future) pregnancy wish.
Complete response to imiquimod occurs in 55-73% of patients, however side-effects of
imiquimod are common and can be extensive. Therefore, 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.
This prospective, multi-center cohort study aims to validate the potential of immune related
biomarkers to predict the clinical response of patients with primary cHSIL to imiquimod, aims
to explore the value of these immune biomarkers in recurrent/residual cHSIL to predict
treatment responses for imiquimod and aims to explore their potential in spontaneous
regression of cHSIL (CIN2).
Detailed Description
RATIONALE: 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 the recent TOPIC-3 trial for cHSIL a complete response rate of 55% upon
imiquimod therapy was reported. 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).
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 their potential in spontaneous regression of cHSIL (CIN2).
STUDY DESIGN: Multicenter, real-life prospective cohort validation study.
STUDY POPULATION: We aim to include 316 women with a primary histological diagnosis of cHSIL,
50 patients with residual/recurrent histological diagnosis of cHSIL treated with imiquimod
and 50 patients with cHSIL (e.g. CIN 2) not treated to await potential spontaneous regression
according to the real life setting.
INTERVENTION: Patients are included in the study if they prefer imiquimod treatment, as
standard care, for their cHSIL lesion or choose for expectative management of cHSIL (e.g.
CIN2), according to the real-life clinical setting in the Netherlands. Patients are treated
by a 16-week regime of imiquimod 5% cream, applied three times a week. Treatment efficacy
will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months
after completion of imiquimod therapy with cytology or if indicated histology. At inclusion,
at 20 weeks and after 6 months a vaginal swab will be taken to evaluate the vaginal
microbiome. Therapy adherence and side effects will be registered.
PRIMARY STUDY OBJECTIVES:
- Confirm the relationship between a complete clinical response to imiquimod and the
increased epithelial and 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 CIBI to a complete response to imiquimod treatment in
primary cHSIL.
- Determine the sensitivity and specificity of CIBI in patients with primary cHSIL lesions
to estimate the predictive value for therapy efficacy upon imiquimod treatment.
SECONDARY STUDY OBJECTIVES:
- Explore the CIBI as a predictive biomarker for therapy efficacy to imiquimod treatment
in patients with residual/recurrent cHSIL (rrcHSIL).
- Explore the CIBI as a predictive biomarker for spontaneous regression of cHSIL (e.g.
CIN2).
- 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 in relation to imiquimod treatment and the relation to spontaneous
regression.
NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP
RELATEDNESS: 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.
Study Type
Observational [Patient Registry]
Primary Outcome
Confirm association of 'hot signature' immune infiltrates in cHSIL with complete clinical responses to imiquimod
Secondary Outcome
Explore the role of CIBI in therapy responses to imiquimod in rrcHSIL
Condition
Cervical High Grade Squamous Intraepithelial Lesion
Intervention
Imiquimod
Study Arms / Comparison Groups
Primary cHSIL
Description: Women with a first diagnosis of cHSIL (e.g. CIN 2 or CIN 3) who prefer treatment with imiquimod.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
410
Start Date
June 1, 2022
Completion Date
December 2026
Primary Completion Date
December 2024
Eligibility Criteria
Inclusion Criteria:
- Primary cHSIL lesions (e.g. CIN3 or CIN 2), histologically confirmed by diagnostic
biopsy Nota bene: In case of CIN 2, 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
group.
- 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 (Papanicolaou) 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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Edith Van Esch, MD, PhD, 040 - 239 93 00, [email protected]
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT05405270
Organization ID
NL79879.100.22
Responsible Party
Principal Investigator
Study Sponsor
Catharina Ziekenhuis Eindhoven
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
Study Sponsor
Edith Van Esch, MD, PhD, Principal Investigator, Catharina Ziekenhuis Eindhoven
Verification Date
June 2022