Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment

NCT05405270 | Recruiting DMC

• 1 other identifier: NL79879.100.22
• Study Type: observational
• Target: 410
• Locations: 1 country
• Sites: 15

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).

Conditions

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

Keywords

Cervical high-grade squamous intraepithelial lesion (cHSIL); Imiquimod; Tumor immunemicroenvironment; High-risk human papilloma virus (hrHPV); Cervical intraepithelial neoplasia (CIN); Biomarker

Outcome Measures

Primary Outcomes (3)

• Confirm association of 'hot signature' immune infiltrates in cHSIL with complete clinical responses to imiquimod

  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.

  Up to 3 years

• Validate immune biomarker CIBI for imiquimod for predicting complete response in cHSIL

  Defined as the sum of the numbers of either epithelial or stromal CD4+/CD11c+/M1+ cells per square millimeter minus the number of FoxP3+ cells per square millimeter, with a complete response to imiquimod treatment in primary cHSIL.

  Up to 3 years

• Determine the sensitivity and specificity of the CIBI in cHSIL

  Determine the sensitivity and specificity of the CIBI in patients with primary cHSIL lesions to estimate the predictive value for therapy efficacy upon imiquimod treatment.

  Up to 3 years

Secondary Outcomes (12)

• Explore the role of CIBI in therapy responses to imiquimod in rrcHSIL

  Up to 3 years

• Explore the role of CIBI in prediction of spontaneous regression of CIN 2

  Up to 3 years

• Determine treatment efficacy upon imiquimod therapy.

  During imiquimod treatment, 20 weeks after start of imiquimod and 6 months after completion of imiquimod treatment

• Determine therapy adherence upon imiquimod therapy.

  During imiquimod treatment (16 weeks)

• Determine reported side effects upon imiquimod therapy.

  During imiquimod treatment (16 weeks)

Study Arms (3)

Primary cHSIL

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

Drug: Imiquimod; Diagnostic Test: 3x vaginal swab for microbiome analysis

Recurrent/residual cHSIL (rrcHSIL)

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

Drug: Imiquimod; Diagnostic Test: 3x vaginal swab for microbiome analysis

CIN 2 observational group

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

Other: Expectative management; Diagnostic Test: 2x vaginal swab for microbiome analysis

Interventions

Imiquimod 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.

Also known as: Aldara

Primary cHSIL; Recurrent/residual cHSIL (rrcHSIL)

3x vaginal swab for microbiome analysis 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.

Primary cHSIL; Recurrent/residual cHSIL (rrcHSIL)

Expectative management OTHER

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

CIN 2 observational group

2x vaginal swab for microbiome analysis DIAGNOSTIC_TEST

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

CIN 2 observational group

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Only patients who have a cervix uteri are eligible.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients will be included in real-life outpatient clinic setting and treated according to standard Dutch therapy guidelines. We aim to enroll 310 patients with primary cHSIL and 50 patients with rrcHSIL treated with imiquimod and 50 cHSIL (CIN 2) patients not treated in the observational arm.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Catharina Ziekenhuis Eindhoven: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Stichting Olijf: Dutch patient association for women with gynaecological cancer: collaborator
• Leids Universitair Medisch Centrum: Department of Medical Oncology and Department of Pathology: collaborator
• Maastricht Universitair Medisch Centrum: Department of Gynaecology and Department of Pathology: collaborator
• Erasmus Medisch Centrum: Department of Gynaecology: collaborator
• Radboud Medisch Centrum: Department of Gynaecology: collaborator

Study Sites (15)

Amphia

Breda, Netherlands

RECRUITING

Albert Schweitzer Ziekenhuis

Dordrecht, Netherlands

RECRUITING

Catharina Ziekenhuis Eindhoven

Eindhoven, Netherlands

RECRUITING

Tergooi MC

Hilversum, Netherlands

RECRUITING

Medisch Centrum Leeuwarden

Leeuwarden, Netherlands

RECRUITING

Leiden Universitair Medisch Centrum

Leiden, Netherlands

NOT YET RECRUITING

Maastricht Universitair Medisch Centrum

Maastricht, Netherlands

RECRUITING

Radboudumc

Nijmegen, Netherlands

RECRUITING

Erasmus Medisch Centrum

Rotterdam, Netherlands

RECRUITING

Franciscus Gasthuis & Vlietland

Rotterdam, Netherlands

RECRUITING

HagaZiekenhuis

The Hague, Netherlands

RECRUITING

Diakonessenhuis

Utrecht, Netherlands

RECRUITING

Máxima MC

Veldhoven, Netherlands

RECRUITING

VieCuri Medisch Centrum

Venlo, Netherlands

RECRUITING

Isala

Zwolle, Netherlands

RECRUITING

Related Publications (10)

• de Witte CJ, van de Sande AJ, van Beekhuizen HJ, Koeneman MM, Kruse AJ, Gerestein CG. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review. Gynecol Oncol. 2015 Nov;139(2):377-84. doi: 10.1016/j.ygyno.2015.08.018. Epub 2015 Aug 31.

  PMID: 26335596 BACKGROUND

• Loopik DL, van Drongelen J, Bekkers RLM, Voorham QJM, Melchers WJG, Massuger LFAG, van Kemenade FJ, Siebers AG. Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes. PLoS Med. 2021 Jun 4;18(6):e1003665. doi: 10.1371/journal.pmed.1003665. eCollection 2021 Jun.

  PMID: 34086680 BACKGROUND

• Hendriks N, Koeneman MM, van de Sande AJM, Penders CGJ, Piek JMJ, Kooreman LFS, van Kuijk SMJ, Hoosemans L, Sep SJS, de Vos Van Steenwijk PJ, van Beekhuizen HJ, Slangen BFM, Nijman HW, Kruitwagen RFPM, Kruse AJ. Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study. J Immunother. 2022 Apr 1;45(3):180-186. doi: 10.1097/CJI.0000000000000414.

  PMID: 35180719 BACKGROUND

• Abdulrahman Z, de Miranda N, van Esch EMG, de Vos van Steenwijk PJ, Nijman HW, J P Welters M, van Poelgeest MIE, van der Burg SH. Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination. J Immunother Cancer. 2020 Mar;8(1):e000563. doi: 10.1136/jitc-2020-000563.

  PMID: 32169871 BACKGROUND

• Abdulrahman Z, de Miranda NFCC, Hellebrekers BWJ, de Vos van Steenwijk PJ, van Esch EMG, van der Burg SH, van Poelgeest MIE. A pre-existing coordinated inflammatory microenvironment is associated with complete response of vulvar high-grade squamous intraepithelial lesions to different forms of immunotherapy. Int J Cancer. 2020 Nov 15;147(10):2914-2923. doi: 10.1002/ijc.33168. Epub 2020 Jul 3.

  PMID: 32574376 BACKGROUND

• Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019 Mar;18(3):197-218. doi: 10.1038/s41573-018-0007-y.

  PMID: 30610226 BACKGROUND

• 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.

  PMID: 35268523 BACKGROUND

• 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.

  PMID: 26574055 BACKGROUND

• 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.

  PMID: 20512116 BACKGROUND

• Loopik DL, Bentley HA, Eijgenraam MN, IntHout J, Bekkers RLM, Bentley JR. The Natural History of Cervical Intraepithelial Neoplasia Grades 1, 2, and 3: A Systematic Review and Meta-analysis. J Low Genit Tract Dis. 2021 Jul 1;25(3):221-231. doi: 10.1097/LGT.0000000000000604.

  PMID: 34176914 BACKGROUND

MeSH Terms

Conditions

Uterine Cervical Dysplasia

Interventions

Imiquimod

Condition Hierarchy (Ancestors)

Precancerous Conditions; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Edith Van Esch, MD, PhD

  Catharina Ziekenhuis Eindhoven

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caroline Muntinga, MD

CONTACT

040 - 239 93 00; predict-topic@catharinaziekenhuis.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, gynaecologist

Study Record Dates

• First Submitted: May 19, 2022
• First Posted: June 6, 2022
• Study Start: June 1, 2022
• Primary Completion: December 1, 2024
• Study Completion (Estimated): December 1, 2026
• Last Updated: September 11, 2023

Record last verified: 2023-09

Locations

NL (15)