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Cervical High Grade Squamous Intraepithelial LesionPRedICT-TOPICNCT05405270

Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment

An observational study of Cervical High Grade Squamous Intraepithelial Lesion and Cervical Intraepithelial Neoplasia Grade 2/3, run by Catharina Ziekenhuis Eindhoven at 15 sites in Netherlands.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Imiquimod, 3x vaginal swab for microbiome analysis and Expectative management
How many people
410 participants
Where
15 sitesNetherlands
Study dates
1 Jun 2022to Dec 2026
How long will I take part?
2 Years
Phase
Observational
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

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.

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 10Show fewer
  • Immunodeficiency (including HIV/AIDS and immunosuppressive medication)
  • Pregnancy
  • Legal incapability
  • Insufficient knowledge of the Dutch language

Trial locations and contacts

15 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Caroline Muntinga, MD contact

040 - 239 93 00

predict-topic@catharinaziekenhuis.nl

15 sites in 1 country

Netherlands15 sites, 15 recruiting

  • Amphia

    Breda

    Dineke Smedts, MD, PhD

    Recruiting

  • Albert Schweitzer Ziekenhuis

    Dordrecht

    Gatske Nieuwenhuyzen, MD, PhD

    Recruiting

  • Catharina Ziekenhuis Eindhoven

    Eindhoven

    Caroline Muntinga, MD, predict-topic@catharinaziekenhuis.nl

    Recruiting

  • Tergooi MC

    Hilversum

    Hélène van Meir, MD, PhD

    Recruiting

  • Medisch Centrum Leeuwarden

    Leeuwarden

    Marjan Keizer, MD

    Recruiting

  • Leiden Universitair Medisch Centrum

    Leiden

    Mariëtte van Poelgeest, MD, PhD

    Not yet recruiting

  • Maastricht Universitair Medisch Centrum

    Maastricht

    Peggy de Vos van Steenwijk, MD, PhD

    Recruiting

  • Radboudumc

    Nijmegen

    Petra Zusterzeel, MD, PhD

    Recruiting

  • Erasmus Medisch Centrum

    Rotterdam

    Heleen van Beekhuizen, MD, PhD

    Recruiting

  • Franciscus Gasthuis & Vlietland

    Rotterdam

    Meike van de Sande, MD

    Recruiting

  • HagaZiekenhuis

    The Hague

    Kevin Voogdt, MD, PhD

    Recruiting

  • Diakonessenhuis

    Utrecht

    Jacqueline Louwers, MD, PhD

    Recruiting

  • Máxima MC

    Veldhoven

    Viola Verhoef, MD, PhD

    Recruiting

  • VieCuri Medisch Centrum

    Venlo

    Rafli van der Laar, MD, PhD

    Recruiting

  • Isala

    Zwolle

    Arnold-Jan Krüse, MD, PhD

    Recruiting

Other trials in Netherlands

About this study

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).

Read the 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.

Being tested
Imiquimod, 3x vaginal swab for microbiome analysis, Expectative management, 2x vaginal swab for microbiome analysis
Keywords
Cervical high-grade squamous intraepithelial lesion (cHSIL), Imiquimod, Tumor immunemicroenvironment, High-risk human papilloma virus (hrHPV), Cervical intraepithelial neoplasia (CIN), Biomarker
Medical subject headings
Uterine Cervical Dysplasia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ImiquimodDrug

    Also called Aldara

    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 analysisDiagnostic 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.

  • Expectative managementOther

    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 analysisDiagnostic test

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

Study groups in NCT05405270
Study groupRoleWhat they receive
Primary cHSILWomen with a first diagnosis of cHSIL (e.g. CIN 2 or CIN 3) who prefer treatment with imiquimod.
Receives: 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.
Receives: Drug: Imiquimod; Diagnostic Test: 3x vaginal swab for microbiome analysis
CIN 2 observational groupWomen with primary CIN 2 who prefer expectant management to await the potential of spontaneous regression.
Receives: Other: Expectative management; Diagnostic Test: 2x vaginal swab for microbiome analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 3 years

  2. 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.

    Measured: Up to 3 years

  3. 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.

    Measured: Up to 3 years

Secondary outcomes (12)

  1. Explore the role of CIBI in therapy responses to imiquimod in rrcHSIL

    Explore the CIBI as a predictive biomarker for therapy efficacy to imiquimod treatment in patients with residual/recurrent cHSIL (rrcHSIL).

    Measured: Up to 3 years

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

    Explore the CIBI as a predictive biomarker for spontaneous regression of cHSIL (e.g. CIN2).

    Measured: Up to 3 years

  3. Determine treatment efficacy upon imiquimod therapy.

    Treatment efficacy will be evaluated by determination of clinical responses at 20 weeks and at 6 months by either complete responder (CR), partial responder (PR), non-responder (NR) or progressive disease (PD) assessed by histology from biopsy and/or cytology from papsmear.

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

  4. Determine therapy adherence upon imiquimod therapy.

    Therapy adherence will be evaluated by patient reported use on the calendar by registrating the amount of imiquimod applications per week.

    Measured: During imiquimod treatment (16 weeks)

  5. Determine reported side effects upon imiquimod therapy.

    Reported side effects will be evaluated by documentation of side effects on the calendar.

    Measured: During imiquimod treatment (16 weeks)

  6. Determine treatment HPV clearance upon imiquimod treatment.

    HPV clearance will be tested according to the absence or presence of hrHPV infection according to the local pathology sites via standard operating procedures.

    Measured: Before start of imiquimod treatment, 20 weeks after start imiquimod treatment, 6 months after completion of imiquimod treatment.

  7. Evaluate maintenance of lesion regression after imiquimod treatment

    Determination of recurrent cHSIL or progression to cervical cancer.

    Measured: 24 months and 5 year follow-up with cytology and histology if necessary

  8. Evaluate time to recurrence or progression of cHSIL.

    Determination of time to recurrence or progression of cHSIL.

    Measured: 24 months and 5 year follow-up with cytology and histology if necessary

  9. Explore and evaluate other potential more specific predictive (immune) biomarkers in cHSIL

    For example dedicated gene expression profiles by Nanostring and gene methylation assays.

    Measured: Up to 3 years

  10. Develop a simplified pathological scoring system

    Explorative development of a simplified dual immunohistochemistry protocol to identify the hot signature and exploration of the predictive value of this 'immunoscore' in cHSIL.

    Measured: Up to 3 years

  11. Validate the CIBI via single immunohistochemistry

    Defined as epithelial or stromal cluster of differentiation (CD) 4+/CD11c+/CD68+ cells per square millimeter with a complete response to imiquimod treatment in primary cHSIL.

    Measured: Up to 3 years

  12. Determine the vaginal microbiome in cHSIL patients

    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.

    Measured: Baseline, 20 weeks after start of imiquimod and 6 months after completion of imiquimod treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jun 2022
  2. Study start1 Jun 2022
  3. Primary completionDec 2024 (estimated)
  4. Study completionDec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
410 participants (estimated)
Target duration
2 Years
IDs, dates and publications
ClinicalTrials.gov ID
NCT05405270
Sponsor's protocol ID
NL79879.100.22
Acronym
PRedICT-TOPIC
Status last verified
Sep 2023
First submitted
19 May 2022
Last updated
11 Sep 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 26335596

  • 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.

    PubMed 34086680

  • 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.

    PubMed 35180719

  • 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.

    PubMed 32169871

  • 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.

    PubMed 32574376

  • 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.

    PubMed 30610226

  • 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.

    PubMed 35268523

  • 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.

    PubMed 26574055

  • 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.

    PubMed 20512116

  • 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.

    PubMed 34176914

Questions about this trial

What is this clinical trial studying?

An observational study of Cervical High Grade Squamous Intraepithelial Lesion and Cervical Intraepithelial Neoplasia Grade 2/3, run by Catharina Ziekenhuis Eindhoven at 15 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 11 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Caroline Muntinga, MD (040 - 239 93 00, predict-topic@catharinaziekenhuis.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Confirm association of 'hot signature' immune infiltrates in cHSIL with complete clinical responses to imiquimod (time frame: Up to 3 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05405270, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2023.

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