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Early Detection of High Grade Ovarian Cancer Using Uterine Lavage EHUD Study and Duplex Sequencing (EHUD)

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ClinicalTrials.gov Identifier: NCT04823871
Recruitment Status : Recruiting
First Posted : April 1, 2021
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Paul Speiser, Prof.MD,, Medical University of Vienna

Brief Summary:
In Phase I the sponsor will systematically test conditions for lavage filtration that increase tumor cell fraction without reducing tumor mutation yield. The Sponsor will also transition all lavages to luteal phase timing, when endometrial shedding is least. In Phase II the Sponsor will examine our data in context of clinical characteristics, particularly age, to develop a multivariate model that determines optimal mutant allele frequency (MAF) diagnostic threshold by patient. Furthermore, the sponsor will explore a highly innovative idea, entailing empirically determining each individual's background mutation load, agnostic of the aging or mutagenic exposures responsible, and using this as a personalized calibrator to determine optimal MAF diagnostic threshold.

Condition or disease Intervention/treatment Phase
Ovarian Epithelial Cancer Carcinoma in Situ Ovarian Cancer Procedure: Speiser-catheter for uterine and tubal lavage Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Case control study in two patient population (AIM 1 in average risk population, AIM 2 in high risk population)
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Pilot Study of Early Detection of High Grade Ovarian Cancer Using Uterine Lavage and Duplex Sequencing
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer

Arm Intervention/treatment
High risk patients for breast and/or ovarian cancer
Procedure/Surgery: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle
Procedure: Speiser-catheter for uterine and tubal lavage
Procedure/Surgery: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle

Suspected Ovarian Epithelial Cancer
Procedure/Surgery: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle
Procedure: Speiser-catheter for uterine and tubal lavage
Procedure/Surgery: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle




Primary Outcome Measures :
  1. Variant allele frequencies (VAF) for variants identified in both unfiltered and filtrate uterine lavage from the same patient. [ Time Frame: Day 1 ]
    Preliminary testing with two samples indicated that filtration of UtLs to remove clusters of endometrial cells could increase sensitivity for tumor mutations several fold. This dataset will be expanded by analyzing the filtration effect in 10 ULs from patients with HGSC with known TP53 mutations. Each UtL will be divided in half: the first half will be filtered and the second will remain unfiltered. DNA will be extracted from the filtered, filtrate, and unfiltered fractions and analyzed by TP53KDS (total of 30 samples). For each UL, the DNA yield will be compared in each of the fractions and the MAF of the tumor mutation. It is anticipated that the filtered fraction will contain less DNA then the unfiltered fraction but the tumor mutation will be present at a higher frequency (i.e. more is gained by enrichment than is lost by reduction from less available DNA).

  2. SNP allele fraction (AF) comparison at different dilutions: expected AF vs. observed AF, AF variation among replicates (UtLs). [ Time Frame: Day 1 ]
    SNP allele fraction (AF) will be compared at different dilutions to determine accuracy (expected AF vs. observed AF), precision (AF variation among replicates), and lowest limit of detection achievable.

  3. Total mutation frequency (UtLs) [ Time Frame: Day 1 ]
    To asses the reproducibility in clinical use total mutation frequency will be assayed. The coefficient of variation among replicates will be calculated. Overall mutation frequency across TP53 in UtLs samples will be measured for both replicates of each patient. VAF will be approximated by number of non-reference duplex bases/total duplex bases sequenced. Confidence intervals will be computed using a binomial normal approximation.

  4. Mutant allele frequency (MAF) for all mutated positions, mutation spectrum (UtLs), [ Time Frame: Day 1 ]

    A detailed mutation profile will be generated from the DS output files: mutant allele frequency (MAF) for all mutated positions, mutation spectrum, predicted pathogenicity to protein function, relationship to known hotspots, and overall mutation load (number of mutant nucleotides divided by the total number of nucleotides sequenced). Following this, samples will be unblinded for cases-controls status.

    TP53 MAF from DNA collected by UtLs will be used as predictor for differentiating between average risk patients (AIM I) with and without HGSC by logistic regression modelling. An analogous analysis will be applied to the group of high risk patients (AIM II) where presence and absence of STIC is defining the outcome variable. Cut off values for mutant allele frequency will be suggested in both cases and specificity and sensitivity will be estimated including appropriate confidence intervals.


  5. TP53 mutation frequencies in leukocytes [ Time Frame: Day 1 ]
    The association between TP53 mutation frequencies in uterine lavage and leukocytes will be examined and will determine whether false negatives in Aim 1A correspond to cases with increased BB in leukocytes. In addition, TP53 mutation frequencies in leukocytes will be analyzed as a predictor of case control status, again using the leave out 10% procedure. This innovative calibration method will be compared with the simple ROC metrics achieved with the univariate model using a fixed mutation fraction as well as the adjusted multivariate model developed based on other patient characteristics such as age. As a scientific question unrelated to the present aims, it is worth investigating whether leukocyte TP53 mutation load will serve as an independent predictor of patient age, overall health or history of mutagenic exposures.

  6. Variant allele frequencies (VAF) for variants identified in uterine lavage ans pap smear from the same patient. [ Time Frame: Day 1 ]
    Comparison of performance of UtL collection with that of Pap smear collection. It will be investigated if any additional power to discriminate cases from controls can be gained by combining information from Pap smears and ULs.

  7. dCT-PCR values from 96-plexed high-throughput MSREqPCR analysis [ Time Frame: Day 1 ]
    Aiming to evaluate the potential for defining a DNA-Methylation signature for simple PCR testing, dCT-PCR values from 96-plexed high-throughput MSREqPCR analysis will be analysed by bioinformatics & biostatistics. See Detailed description og the Aim III above for more details.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent obtained
  • Age ≥ 18 years and ≤ 80 years
  • Women undergoing primary surgery for suspected High grade serous carcinoma (HGSC) If premenopausal in luteal phase (minimum 14 days after last day of menstrual period) or:
  • Women with high risk for breast or ovarian cancer (HBOC) undergoing prophylactic resection of tubes with or without ovaries. If premenopausal in luteal phase except amenorrhea under hormonal contraception (incl. levonorgestrel -IUD)

Exclusion Criteria:

  • Incapacitated women
  • Pregnant women
  • Prior hysterectomy
  • Prior bilateral salpingectomy
  • Prior tubal ligation
  • First half of menstrual cycle
  • Interval debulking
  • Current cytotoxic chemotherapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04823871


Contacts
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Contact: Paul Speiser 06765536415 paul.speiser@meduniwien.ac.at
Contact: Claudia Duwe claudia.duwe@meduniwien.ac.at

Locations
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Austria
Medizinische Universität Graz Recruiting
Graz, Austria
Contact: Gunda Pristauz-Telsnigg, Prof. Dr.med.       gunda.pristauz@klinikum-graz.at   
Medical University Innsbruck Not yet recruiting
Innsbruck, Austria
Contact: Christian Marth, Prof. Dr.       christian.marth@tirol-kliniken.at   
Contact: Regina Berger, DR.       regina.berger@tirol-kliniken.at   
Kepler Universitätsklinikum Linz Not yet recruiting
Linz, Austria
Contact: Christina Anreiter, Dr.med.       christina.anreiter@kepleruniklinikum.at   
Medical University Vienna, Dptm. of Obstetrics & Gynaecology Recruiting
Vienna, Austria, 1090
Contact: Paul Speiser, Prof., M.D.    +436765367608    paul.speiser@meduniwien.ac.at   
Contact: Claudia Duwe    +436765536415    claudia.duwe@meduniwien.ac.at   
Czechia
Masaryk Memorial Cancer Institute Brno Recruiting
Brno, Czechia
Contact: Gabriel Jelenek       gabrieljelenek@gmail.com   
Charles University Prag Recruiting
Prague, Czechia
Contact: David Cibula       dc@davidcibula.cz   
Contact: Lukas Dostalek       Lukas.Dostalek@vfn.cz   
Germany
University Hospital Bonn Recruiting
Bonn, Germany
Contact: Alexander Mustea, Prof.Dr.med.       alexander.mustea@ukbonn.de   
Contact: Mateja Condic, Dr.med.       Mateja.Condic@ukbonn.de   
Gynaecological Clinic TU of Munich Not yet recruiting
München, Germany
Contact: Sabine Grill, DR.med       Sabine.Grill@mri.tum.de   
Ireland
St. James Hospital Not yet recruiting
Dublin, Ireland
Contact: Noreen Gleeson       'noreengleeson@dubgyn.org'   
Sponsors and Collaborators
Paul Speiser, Prof.MD,
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Responsible Party: Paul Speiser, Prof.MD,, Clinical Professor, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT04823871    
Other Study ID Numbers: EK 1612/2018
First Posted: April 1, 2021    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Paul Speiser, Prof.MD,, Medical University of Vienna:
Ovarian Epithelial Cancer f
Serous Intraepithelial Carcinoma (STIC)
BRCA1 gene Mutation
BRCA2 gene Mutation
Neoplasms
Glandular and Epithelial
Ovarian Neoplasms
Ovarian cancer
Carcinoma in situ
Family history breast cancer and ovarian cancer
Additional relevant MeSH terms:
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Carcinoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Carcinoma in Situ
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders