Imiquimod Treatment of CIN Lesions

NCT02329171 | Terminated Phase 3 DMC

• 1 other identifier: METC 13-2-031
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Cervical Intraepithelial Neoplasia (CIN) is the premalignant condition of cervical cancer. High grade CIN (CIN 2-3) is currently treated by large loop excision of the transformation zone (LLETZ). This treatment has potential complications, such as hemorrhage, infection and preterm birth in subsequent pregnancies. For this reason, non-invasive therapies are needed. Imiquimod (an immunomodulator) was proven effective in the treatment of HPV-related vulvar intraepithelial neoplasia (VIN) and may also be effective in HPV-related CIN. \[van Seters, 2012\] However, the evidence is limited and study results are not consistent. \[Grimm, 2012; Pachman, 2012; Lin, 2012\] Objectives: Primary objectives: (1) to investigate the efficacy of imiquimod 5% cream for the treatment of CIN2-3 lesions and (2) to develop biomarker panels to predict clinical response to imiquimod therapy. Secondary objectives: to assess side effects of imiquimod treatment and LLETZ, disease recurrence and quality of life. Hypothesis: The investigators hypothesize that imiquimod will be an effective treatment modality in approximately 50-75% of CIN lesions treated without surgical intervention. Study design: Single-centre randomized controlled intervention trial. Study population: 140 women with a histological diagnosis of CIN2-3, equally divided over two study arms. Intervention: Patients will be randomized into one of two arms:

1. 1.Imiquimod treatment arm. Patients in this group are treated by a 16-week regime of imiquimod 5% cream.
2. 2.Standard treatment arm. LLETZ will be performed on patients in this group.

Conditions

Cervical Intraepithelial Neoplasia

Outcome Measures

Primary Outcomes (2)

• Treatment efficacy: histological disease regression

  Defined as following: * for imiquimod treatment arm: CIN1 or less in diagnostic biopsies at colposcopy at 20 weeks * for LLETZ arm: PAP 1 at 6 months follow-up

  20 weeks

• Baseline biomarker profile predicting clinical response to imiquimod treatment

  The biomarker profiles will consist of markers reflecting host and viral factors, including HPV-genotype, markers of immunologic response (CD4, CD8, CD25, CD138, Fox p3) and markers of cell cycle processes (Rb, p53, Ki67, CK 13/14, IMP3).

  20 weeks

Secondary Outcomes (3)

• Prevalence and severity of side effects of imiquimod and LLETZ treatment

  6 weeks, 10 weeks, 14 weeks and 20 weeks for imiquimod treatment and 6 weeks for LLETZ treatment

• Quality of life for all treatment groups.

  Baseline, 20 weeks and 1 year

• Disease recurrence for all treatment groups.

  6, 12 and 24 months

Study Arms (2)

Imiquimod treatment arm

EXPERIMENTAL

Patients in this group will be treated with imiquimod during 16 weeks. Colposcopy with diagnostic biopsies will be performed after 10 weeks. In case of progressive disease, the treatment will be ended and appropriate surgical excision will be performed. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies.

Drug: Imiquimod

Standard treatment arm

ACTIVE COMPARATOR

Large loop excision of the transformation zone (LLETZ) will be performed in this group, as standard treatment.

Procedure: LLETZ

Interventions

Imiquimod DRUG

Imiquimod 5% cream will be administered in a vaginal applicator, containing 12,5 mg of imiquimod (one sachet). The cream will be self-administered three times per week, by use of a vaginal applicator.

Also known as: Imiquimod, Aldara.

Imiquimod treatment arm

LLETZ PROCEDURE

Standard treatment consists of a LLETZ procedure, in which excision of the transformation zone and macroscopic lesions is performed by a monopolar loop electrode, under local anaesthesia. The excision is usually performed in two or three steps, depending on the size of the lesions.

Also known as: Loop excision

Standard treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• newly diagnosed high grade CIN lesions (CIN 2-3), histologically confirmed
• age 18 years or older

You may not qualify if:

• immunodeficiency
• pregnancy or lactation
• legally incapability
• history of histologically conformed high-grade CIN

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• MEDA Pharma GmbH & Co. KG: collaborator

Study Sites (1)

Maastricht University Medical Centre

Maastricht, 6202AZ, Netherlands

Location

Related Publications (18)

• van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008 Apr 3;358(14):1465-73. doi: 10.1056/NEJMoa072685.

  PMID: 18385498 BACKGROUND

• Grimm C, Polterauer S, Natter C, Rahhal J, Hefler L, Tempfer CB, Heinze G, Stary G, Reinthaller A, Speiser P. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol. 2012 Jul;120(1):152-9. doi: 10.1097/AOG.0b013e31825bc6e8.

  PMID: 22914404 BACKGROUND

• Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, Sloan JA, Loprinzi CL, Gostout BS. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012 Jan;206(1):42.e1-7. doi: 10.1016/j.ajog.2011.06.105. Epub 2011 Jul 13.

  PMID: 21907959 BACKGROUND

• Lin CT, Qiu JT, Wang CJ, Chang SD, Tang YH, Wu PJ, Jung SM, Huang CC, Chou HH, Jao MS, Lai CH. Topical imiquimod treatment for human papillomavirus infection in patients with and without cervical/vaginal intraepithelial neoplasia. Taiwan J Obstet Gynecol. 2012 Dec;51(4):533-8. doi: 10.1016/j.tjog.2012.09.006.

  PMID: 23276555 BACKGROUND

• Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, Haywood M, Elanko N, Coleman D, Yule R, Desai M. Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort. Br J Cancer. 2004 Aug 31;91(5):942-53. doi: 10.1038/sj.bjc.6602049.

  PMID: 15292939 BACKGROUND

• McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. doi: 10.1016/S1470-2045(08)70103-7. Epub 2008 Apr 11.

  PMID: 18407790 BACKGROUND

• Canfell K, Barnabas R, Patnick J, Beral V. The predicted effect of changes in cervical screening practice in the UK: results from a modelling study. Br J Cancer. 2004 Aug 2;91(3):530-6. doi: 10.1038/sj.bjc.6602002.

  PMID: 15266332 BACKGROUND

• Follen M, Atkinson EN, Schottenfeld D, Malpica A, West L, Lippman S, Zou C, Hittelman WN, Lotan R, Hong WK. A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix. Clin Cancer Res. 2001 Nov;7(11):3356-65.

  PMID: 11705848 BACKGROUND

• Meyskens FL Jr, Surwit E, Moon TE, Childers JM, Davis JR, Dorr RT, Johnson CS, Alberts DS. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst. 1994 Apr 6;86(7):539-43. doi: 10.1093/jnci/86.7.539.

  PMID: 8133537 BACKGROUND

• Keefe KA, Schell MJ, Brewer C, McHale M, Brewster W, Chapman JA, Rose GS, McMeeken DS, Lagerberg W, Peng YM, Wilczynski SP, Anton-Culver H, Meyskens FL, Berman ML. A randomized, double blind, Phase III trial using oral beta-carotene supplementation for women with high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2001 Oct;10(10):1029-35.

  PMID: 11588128 BACKGROUND

• Alvarez RD, Conner MG, Weiss H, Klug PM, Niwas S, Manne U, Bacus J, Kagan V, Sexton KC, Grubbs CJ, Eltoum IE, Grizzle WE. The efficacy of 9-cis-retinoic acid (aliretinoin) as a chemopreventive agent for cervical dysplasia: results of a randomized double-blind clinical trial. Cancer Epidemiol Biomarkers Prev. 2003 Feb;12(2):114-9.

  PMID: 12582020 BACKGROUND

• Garcia F, Petry KU, Muderspach L, Gold MA, Braly P, Crum CP, Magill M, Silverman M, Urban RG, Hedley ML, Beach KJ. ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2004 Feb;103(2):317-26. doi: 10.1097/01.AOG.0000110246.93627.17.

  PMID: 14754702 BACKGROUND

• Van Pachterbeke C, Bucella D, Rozenberg S, Manigart Y, Gilles C, Larsimont D, Vanden Houte K, Reynders M, Snoeck R, Bossens M. Topical treatment of CIN 2+ by cidofovir: results of a phase II, double-blind, prospective, placebo-controlled study. Gynecol Oncol. 2009 Oct;115(1):69-74. doi: 10.1016/j.ygyno.2009.06.042. Epub 2009 Aug 3.

  PMID: 19647859 BACKGROUND

• Kaufmann AM, Nieland JD, Jochmus I, Baur S, Friese K, Gabelsberger J, Gieseking F, Gissmann L, Glasschroder B, Grubert T, Hillemanns P, Hopfl R, Ikenberg H, Schwarz J, Karrasch M, Knoll A, Kuppers V, Lechmann M, Lelle RJ, Meissner H, Muller RT, Pawlita M, Petry KU, Pilch H, Walek E, Schneider A. Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer. 2007 Dec 15;121(12):2794-800. doi: 10.1002/ijc.23022.

  PMID: 17721997 BACKGROUND

• Trimble CL, Piantadosi S, Gravitt P, Ronnett B, Pizer E, Elko A, Wilgus B, Yutzy W, Daniel R, Shah K, Peng S, Hung C, Roden R, Wu TC, Pardoll D. Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype. Clin Cancer Res. 2005 Jul 1;11(13):4717-23. doi: 10.1158/1078-0432.CCR-04-2599.

  PMID: 16000566 BACKGROUND

• Munk AC, Gudlaugsson E, Ovestad IT, Lovslett K, Fiane B, Hidle Bv, Kruse AJ, Skaland I, Janssen EA, Baak JP. Interaction of epithelial biomarkers, local immune response and condom use in cervical intraepithelial neoplasia 2-3 regression. Gynecol Oncol. 2012 Dec;127(3):489-94. doi: 10.1016/j.ygyno.2012.09.010. Epub 2012 Sep 24.

  PMID: 23017821 BACKGROUND

• Koeneman MM, Kruse AJ, Kooreman LF, Zur Hausen A, Hopman AH, Sep SJ, Van Gorp T, Slangen BF, van Beekhuizen HJ, van de Sande AJ, Gerestein CG, Nijman HW, Kruitwagen RF. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial. BMC Cancer. 2017 Feb 7;17(1):110. doi: 10.1186/s12885-017-3108-9.

  PMID: 28173776 DERIVED

• Koeneman MM, Kruse AJ, Kooreman LFS, Zur Hausen A, Hopman AHN, Sep SJS, Van Gorp T, Slangen BFM, van Beekhuizen HJ, van de Sande M, Gerestein CG, Nijman HW, Kruitwagen RFPM. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 2016 Feb 20;16:132. doi: 10.1186/s12885-016-2187-3.

  PMID: 26897518 DERIVED

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

• Arnold J Kruse, MD, PhD

  Maastricht University Medical Center

  STUDY DIRECTOR

• R.F.P.M. Kruitwagen, Professor

  Maastricht University Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2014
• First Posted: December 31, 2014
• Study Start: December 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: August 15, 2018

Record last verified: 2016-06

Locations

NL (1)