Clinical trial NCT05051722: Leveraging Methylated DNA Markers (MDMs) in the Detection of Endometrial Cancer, Ovarian Cancer, and Cervical Cancer
Official title: Leveraging Methylated DNA Markers (MDMs) in the Detection of Endometrial Cancer, Ovarian Cancer, and Cervical Cancer: a Phase II Clinical Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Endometrial Cancer
Cervical Cancer
Atypical Endometrial Hyperplasia
Cervical Dysplasia
Adnexal Mass
Ovarian Cancer
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2021-09-21
Enrollment: 3110
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients presenting to a GYN or GYN Surgery Clinic for evaluation of symptoms or for consultation and planned procedures as outlined in the seven study cohort descriptions.

Brief summary: The overarching objective of this project is to develop a pan-gynecologic cancer detection test using gynecologic (unique endometrial, cervical, and ovarian cancer) cancer-specific methylated DNA markers and high-risk human papilloma virus (HR-HPV) detected in vaginal fluid and/or plasma.

This proposal defines Phase II MDM-based cancer detection studies in endometrial cancer (EC) and endometrial hyperplasia with atypia (AEH) in vaginal fluid and 2) ovarian cancer (OC) in plasma and vaginal fluid. Additionally, it defines necessary Phase I MDM-based cancer detection and exploratory aims to test novel cervical cancer (CC) MDMs and test the specificity of cancer-specific MDMs among various common benign gynecologic pathologies.er detection and exploratory aims to test novel cervical cancer MDMs and test the specificity of cancer-specific MDMs among various common benign gynecologic pathologies.

Detailed description: Detection of endometrial, ovarian, and cervical cancers at an early stage vastly increases the chances of cure and may also avert morbidity secondary to surgical staging, radiation, and/or chemotherapy. Despite the great successes of cervical cancer screening, comparable early detection methods for other gynecologic cancers and their precursors are not available. While nearly 1.5 million women per year in the United States are evaluated for abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB), the most common symptom of endometrial cancer, most undergo an invasive diagnostic biopsy with the finding of benign etiology.

Vaginal bleeding is often the only presenting symptom of women ultimately diagnosed with endometrial cancer (EC) or its precursor lesion, endometrial hyperplasia(EH). More than 90% of women with EC present with vaginal bleeding. Cervical cancer and cervical dysplasia can present as intermenstrual bleeding, post-coital bleeding, or other abnormal vaginal bleeding. However, most women who present with AUB or PMB have a benign etiology.

There are approximately 70 million women ≥45 years of age in the United States based on the most recent census data. Between 4-11% of women will be worked up for perimenopausal AUB or PMB in their lifetime. As only 5-10% of those women will have an EC or EH, there is a great clinical need for a less invasive clinical diagnostic test that can reliably distinguish between benign uterine bleeding and bleeding associated with an underlying endometrial cancer, cervical cancer, or a precursor lesion.

Eligibility criteria: Inclusion Criteria for Cohort 1:

Patients will be ≥45 years of age and meet one of the following criteria:

* Abnormal uterine bleeding
* Postmenopausal bleeding

OR

Patients ages 18 - 44 years of age and meet these criteria

* Abnormal uterine bleeding
* One risk factor for endometrial cancer (BMI ≥30 or PCOS or Tamoxifen use)

Exclusion Criteria for Cohort 1:

* Prior hysterectomy
* Current known pregnancy diagnosis
* Any prior pelvic or vaginal radiotherapy
* Any prior cancer (except basal cell skin cancer) within the past 5 years
* Chemotherapy within the past 5 years
* Current biopsy-proven cervical, vaginal, or vulvar cancer or lower genital tract dysplasia
* Current biopsy-proven endometrial cancer or endometrial hyperplasia
* Current biopsy-proven benign endometrial polyp
* Endometrial biopsy/sampling within the preceding 1 month showing benign endometrium

Inclusion Criteria for Cohort 2:

Patients will be ≥18 years of age and meet at least one of the following criteria:

* Presence of biopsy-proven EC (any histology, including uterine carcinosarcoma) and surgical intervention planned. Surgical intervention can include any of the following: hysterectomy, D\&C, hysteroscopic resection
* Biopsy showing AEH or EIN with surgical intervention planned. Surgical intervention can include any of the following: hysterectomy, D\&C, hysteroscopic resection, etc)

Exclusion Criteria for Cohort 2:

* Undergoing surgical procedure for recurrent or metastatic EC
* Received preoperative neoadjuvant chemotherapy or radiotherapy for current EC diagnosis
* Prior hysterectomy
* Current known pregnancy diagnosis
* Prior or current biopsy-proven cervical cancer
* Presence of concomitant biopsy-proven cervical dysplasia
* Any prior pelvic or vaginal radiotherapy
* Any prior cancer (except basal cell skin cancer) within the past 5 years
* Chemotherapy within the past 5 years
* Prior intervention or surgery with intent to completely remove the target pathology

Inclusion Criteria for Cohort 3:

Patients will be ≥18 years of age, have a cervix and meet at least one of the following criteria:

* History of current abnormal cervical/endocervical Pap test for which the patient is presenting for colposcopy
* Cervical mass identified on physical exam and patient referred for cervical biopsy, even if colposcopy not recommended or indicated
* Planned clinically indicated surgical excisional biopsy or removal of the cervix (cold knife cone, LEEP, hysterectomy) for abnormal Pap test, cervical dysplasia, cervical mass, or biopsy-proven invasive cervical cancer (adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, or less common primary cervical carcinomas all eligible)

Exclusion Criteria for Cohort 3:

* History of pelvic or vaginal radiotherapy
* Prior total hysterectomy (cervix removed) for any indication
* Current known pregnancy diagnosis
* Cervical mass biopsy-proven to be EC or a cancer metastatic from a non-cervical origin
* Any prior cancer (except basal cell skin cancer) within the past 5 years
* Chemotherapy within the past 5 years
* Patients presenting for colposcopy as part of lower genital tract dysplasia or cancer surveillance after prior curative intent treatment and no current Pap abnormality or cervical mass
* Prior intervention or surgery with intent to completely remove the target pathology for the current lesion / diagnosis during the current episode

Inclusion Criteria for Cohort 4:

Patients will be ≥45 years of age and should meet at least one of the following criteria:

* Undergoing hysterectomy with biopsy-proven or clinically presumed (based on imaging and/or clinical symptoms) benign gynecologic or uterine pathology of fibroids, endometriosis, adenomyosis, or benign endometrial polyps.
* Undergoing any gynecologic surgery in which a benign pathologic tissue diagnosis of fibroids, endometriosis, adenomyosis, or benign endometrial polyp is anticipated to be confirmed.

Exclusion Criteria for Cohort 4:

* Endometrial biopsy or office hysteroscopy within 2 weeks preceding the planned gynecologic surgery procedure for fibroids, endometriosis, benign endometrial polyps, or adenomyosis
* Any surgery within the past 3 months
* Prior hysterectomy
* Current known pregnancy diagnosis
* Prior or current biopsy-proven gynecologic cancer
* Current biopsy-proven AEH/EIN, cervical, vaginal, or vulvar dysplasia
* Prior pelvic or vaginal radiotherapy
* Any prior cancer (except basal cell skin cancer) within the past 5 years
* Chemotherapy within the past 5 years
* Undergoing hysterectomy for prolapse without a coexisting known or presumed benign uterine pathologic diagnosis of fibroids, endometriosis, benign endometrial polyps, or adenomyosis
* Prior intervention or surgery with intent to completely remove the target pathology for the current lesion / diagnosis during the current episode

Inclusion Criteria for Cohort 5:

Patients with a uterus will be ≥45 years of age and should meet the following criteria:

* Presenting for GYN wellness exam, ± Pap test
* No change in medical conditions, new diagnoses, or new medications within the past 6 months

Exclusion Criteria for Cohort 5:

* Pap test or cervical biopsy within the past 1 month
* Endometrial biopsy or office hysteroscopy within the past 1 month
* Any surgery within the past 3 months
* Prior hysterectomy
* Current known pregnancy diagnosis
* Prior or current biopsy-proven gynecologic cancer
* Current biopsy-proven AEH/EIN, cervical, vaginal, or vulvar dysplasia
* Prior pelvic or vaginal radiotherapy
* Any prior cancer (except basal cell skin cancer) within the past 5 years
* Chemotherapy within the past 5 years
* Criteria met for inclusion in any of the other study cohorts

Inclusion Criteria for Cohort 6:

Patients ≥50 years of age and:

* Postmenopausal
* At least 1 intact ovary
* Diagnosis of an adnexal mass or a clinical suspicion of early-stage ovarian cancer (including fallopian tube cancer)
* Planned surgery for the adnexal mass
* For vaginal fluid collection, patient must have a uterus, cervix and at least 1 intact fallopian tube\* (without prior tubal ligation/occlusion)

Exclusion criteria for Cohort 6:

* Any current or prior cancer diagnosis (except basal cell or squamous cell skin cancer, non-gyn)
* Chemotherapy for cancer treatment within the past 5 years prior to collection
* Clinically suspected advanced stage ovarian cancer (Stage III or IV) on presentation, if known prior to specimen collection
* Surgical candidates for recurrent ovarian cancer
* History of pelvic or vaginal radiation therapy
* Known current synchronous endometrial cancer or hyperplasia
* Known current cervical, vaginal, or vulvar dysplasia

Inclusion criteria for Cohort 7:

Women will be ≥18 years of age and meet the following criteria:

* Presence of clinically probable ovarian, fallopian tube, or primary peritoneal cancer (all under the umbrella of OC) based on clinical findings of any/all of the following: imaging showing adnexal and/or abdominal masses consistent with probable ovarian cancer, omental caking, elevated CA125, ascites, imaging-guided biopsy consistent with OC pathology
* Newly diagnosed with ovarian, fallopian tube or primary peritoneal cancer without neoadjuvant therapy
* At least one intact ovary
* For vaginal fluid collection, patient must have a uterus, cervix and at least 1 intact fallopian tube\* (without prior tubal ligation/occlusion)

Exclusion criteria for Cohort 7:

* Patients with recurrent OC
* Any current or prior cancer diagnosis (except basal cell or squamous cell skin cancer, non-gyn) within the past 5 years
* Chemotherapy for cancer treatment within the past 5 years prior to collection
* History of pelvic or vaginal radiation therapy
* Known current synchronous endometrial cancer or hyperplasia
* Known current cervical, vaginal, or vulvar dysplasia
* Current known pregnancy diagnosis

Primary outcomes:
measure: Develop predictive models from a panel of EC-specific MDMs and validate their performance in identifying underlying EC and AEH within vaginal fluid in a larger, more diverse cohort.
timeFrame: 18 months
measure: Develop predictive models from a panel of OC-specific MDMs and validate their performance in identifying underlying OC within vaginal fluid and plasma in a larger, more diverse cohort.
timeFrame: 18 months
Secondary outcomes:
measure: Using 95% specificity cutoffs of the final MDM EC panel, determine the false positive rate among women undergoing surgical removal of common benign gynecologic pathology
timeFrame: 18 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: My GYN Care
state: Florida
city: Miami
country: United States
facility: Genoma Research, Inc.
state: Florida
city: Pembroke Pines
country: United States
facility: Signature Women's Healthcare, LLC
state: Florida
city: Sarasota
country: United States
facility: Sarasota Memorial Health Care System
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Evergreen Park
country: United States
facility: Providea Health Partners, LLC
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Saginaw
country: United States
facility: Valley OB-GYN Clinic
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Howard Beach
country: United States
facility: The Woman's Health Pavilion
state: New York
city: Westbury
country: United States
facility: The Woman's Health Pavilion
state: New York
city: Grand Forks
country: United States
facility: Altru Health System
state: North Dakota
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Katy
country: United States
facility: Medical Colleagues of Texas, LLP
state: Texas
city: Eau Claire
country: United States
facility: Mayo Clinic Health System - Northwest Wisconsin
state: Wisconsin
city: La Crosse
country: United States
facility: Mayo Clinic Health System - Southwest Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Jamie N Bakkum-Gamez, M.D.
role: PRINCIPAL_INVESTIGATOR
References: