Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment

NCT ID: NCT05405270

Last Updated: 2023-09-11

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 410 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-06-01
• Study Completion Date: 2026-12-31

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.

Conditions

Cervical High Grade Squamous Intraepithelial Lesion; Cervical Intraepithelial Neoplasia Grade 2/3; CIN 2/3; Cervical Intraepithelial Neoplasia

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Primary cHSIL

Women with a first diagnosis of cHSIL (e.g. CIN 2 or CIN 3) who prefer treatment with imiquimod.

Imiquimod

Intervention Type: DRUG

Imiquimod 5% will be administered in the evening by either a vaginal applicator or administered on a vaginal tampon for three times a week during 16 weeks. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months after completion of imiquimod therapy with cytology and if indicated histology.

3x vaginal swab for microbiome analysis

Intervention Type: DIAGNOSTIC_TEST

A vaginal swab will be taken from all patients at inclusion (before start of imiquimod), at colposcopy 20 weeks after start of imiquimod and at 6 months after completion of imiquimod treatment during follow-up appointment.

Recurrent/residual cHSIL (rrcHSIL)

Women who were treated for cHSIL before, but who have a residual or recurrent lesion and prefer treatment with imiquimod.

Imiquimod

Intervention Type: DRUG

Imiquimod 5% will be administered in the evening by either a vaginal applicator or administered on a vaginal tampon for three times a week during 16 weeks. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months after completion of imiquimod therapy with cytology and if indicated histology.

3x vaginal swab for microbiome analysis

Intervention Type: DIAGNOSTIC_TEST

A vaginal swab will be taken from all patients at inclusion (before start of imiquimod), at colposcopy 20 weeks after start of imiquimod and at 6 months after completion of imiquimod treatment during follow-up appointment.

CIN 2 observational group

Women with primary CIN 2 who prefer expectant management to await the potential of spontaneous regression.

Expectative management

Intervention Type: OTHER

Expectative management of CIN 2 when preferred by the patient. Follow-up 6 months after baseline colposcopy with cytology and if indicated histology.

2x vaginal swab for microbiome analysis

Intervention Type: DIAGNOSTIC_TEST

A vaginal swab will be taken from all patients at inclusion and at 6 months after inclusion during follow-up appointment.

Interventions

Imiquimod

Imiquimod 5% will be administered in the evening by either a vaginal applicator or administered on a vaginal tampon for three times a week during 16 weeks. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months after completion of imiquimod therapy with cytology and if indicated histology.

Intervention Type: DRUG

3x vaginal swab for microbiome analysis

A vaginal swab will be taken from all patients at inclusion (before start of imiquimod), at colposcopy 20 weeks after start of imiquimod and at 6 months after completion of imiquimod treatment during follow-up appointment.

Intervention Type: DIAGNOSTIC_TEST

Expectative management

Expectative management of CIN 2 when preferred by the patient. Follow-up 6 months after baseline colposcopy with cytology and if indicated histology.

Intervention Type: OTHER

2x vaginal swab for microbiome analysis

A vaginal swab will be taken from all patients at inclusion and at 6 months after inclusion during follow-up appointment.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

Aldara

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Stichting Olijf: Dutch patient association for women with gynaecological cancer

UNKNOWN

Sponsor Role: collaborator

Leids Universitair Medisch Centrum: Department of Medical Oncology and Department of Pathology

UNKNOWN

Sponsor Role: collaborator

Maastricht Universitair Medisch Centrum: Department of Gynaecology and Department of Pathology

UNKNOWN

Sponsor Role: collaborator

Erasmus Medisch Centrum: Department of Gynaecology

UNKNOWN

Sponsor Role: collaborator

Radboud Medisch Centrum: Department of Gynaecology

UNKNOWN

Sponsor Role: collaborator

Catharina Ziekenhuis Eindhoven

OTHER

Sponsor Role: lead

Responsible Party

Edith van Esch

Principal Investigator, gynaecologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Edith Van Esch, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Catharina Ziekenhuis Eindhoven

Locations

Amphia

Breda, , Netherlands

Site Status: RECRUITING

Albert Schweitzer Ziekenhuis

Dordrecht, , Netherlands

Site Status: RECRUITING

Catharina Ziekenhuis Eindhoven

Eindhoven, , Netherlands

Site Status: RECRUITING

Tergooi MC

Hilversum, , Netherlands

Site Status: RECRUITING

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Site Status: RECRUITING

Leiden Universitair Medisch Centrum

Leiden, , Netherlands

Site Status: NOT_YET_RECRUITING

Maastricht Universitair Medisch Centrum

Maastricht, , Netherlands

Site Status: RECRUITING

Radboudumc

Nijmegen, , Netherlands

Site Status: RECRUITING

Erasmus Medisch Centrum

Rotterdam, , Netherlands

Site Status: RECRUITING

Franciscus Gasthuis & Vlietland

Rotterdam, , Netherlands

Site Status: RECRUITING

HagaZiekenhuis

The Hague, , Netherlands

Site Status: RECRUITING

Diakonessenhuis

Utrecht, , Netherlands

Site Status: RECRUITING

Máxima MC

Veldhoven, , Netherlands

Site Status: RECRUITING

VieCuri Medisch Centrum

Venlo, , Netherlands

Site Status: RECRUITING

Isala

Zwolle, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Caroline Muntinga, MD

Role: CONTACT

predict-topic@catharinaziekenhuis.nl

040 - 239 93 00

Facility Contacts

Dineke Smedts, MD, PhD

Role: primary

Gatske Nieuwenhuyzen, MD, PhD

Role: primary

Caroline Muntinga, MD

Role: primary

predict-topic@catharinaziekenhuis.nl

Hélène van Meir, MD, PhD

Role: primary

Marjan Keizer, MD

Role: primary

Mariëtte van Poelgeest, MD, PhD

Role: primary

Peggy de Vos van Steenwijk, MD, PhD

Role: primary

Petra Zusterzeel, MD, PhD

Role: primary

Heleen van Beekhuizen, MD, PhD

Role: primary

Meike van de Sande, MD

Role: primary

Kevin Voogdt, MD, PhD

Role: primary

Jacqueline Louwers, MD, PhD

Role: primary

Viola Verhoef, MD, PhD

Role: primary

Rafli van der Laar, MD, PhD

Role: primary

Arnold-Jan Krüse, MD, PhD

Role: primary

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Muntinga CLP, de Vos van Steenwijk PJ, Bekkers RLM, van Esch EMG. Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy. J Clin Med. 2022 Mar 5;11(5):1432. doi: 10.3390/jcm11051432.

Reference Type: BACKGROUND

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Mitra A, MacIntyre DA, Lee YS, Smith A, Marchesi JR, Lehne B, Bhatia R, Lyons D, Paraskevaidis E, Li JV, Holmes E, Nicholson JK, Bennett PR, Kyrgiou M. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci Rep. 2015 Nov 17;5:16865. doi: 10.1038/srep16865.

Reference Type: BACKGROUND

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Ovestad IT, Gudlaugsson E, Skaland I, Malpica A, Kruse AJ, Janssen EA, Baak JP. Local immune response in the microenvironment of CIN2-3 with and without spontaneous regression. Mod Pathol. 2010 Sep;23(9):1231-40. doi: 10.1038/modpathol.2010.109. Epub 2010 May 28.

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Other Identifiers

NL79879.100.22

Identifier Type: -

Identifier Source: org_study_id