Signatera Assessment in Early-Stage Endometrial Cancer

NCT07339384 | Not Yet Recruiting FDA Device

• 1 other identifier: 25-102-NCP
• Study Type: interventional
• Target: 1,010
• Locations: 1 country
• Sites: 9

Brief Summary

The goal of this clinical trial is to assess if circulating tumor DNA can guide adjuvant selection in high-intermediate risk early-stage endometrial cancer. The main question it aims to answer is:

• To evaluate if 3-year recurrence-free survival among women with Stage I, high-intermediate risk endometrial cancer who are ctDNA negative after receiving ctDNA-guided observation is non-inferior to adjuvant vaginal brachytherapy (an internal radiation therapy) Researchers will compare high-risk intermediate ctDNA negative participants who are observed to those who receive vaginal brachytherapy to see if they have similar outcomes. Participants will be asked to:
• Receive serial ctDNA testing
• Visit their study doctor per their standard of care visits about every 3 months for 2 years
• Answer a questionnaire about their well-being

Conditions

Endometrial Cancer

Keywords

ctDNA; Endometrial Cancer; circulating tumor; Signatera; Molecular Residual Disease; MRD; biomarker-guided therapy; Vaginal Brachytherapy; VBT; High-Intermediate Risk Endometrial Cancer; Adjuvant Therapy; Tumor-informed assay

Outcome Measures

Primary Outcomes (1)

• Recurrence Free Survival (RFS)

  The primary objective of this study is to evaluate if recurrence free survival (RFS) is non-inferior among women with stage I high-intermediate risk endometrial cancer who are ctDNA-negative after surgery and managed with ctDNA-guided observation versus adjuvant VBT.

  3 years from randomization to the first occurrence of disease recurrence or death from any cause, whichever occurs first

Secondary Outcomes (3)

• Overall Survial

  From enrollment to Year 3 and enrollment to Year 5

• ctDNA Clearance Rate

  From enrollment until first surveillance visit at 12 weeks

• Clinicopathologic and Molecular Risk Factors

  Up to 5 years from enrollment

Other Outcomes (10)

• Lead time of ctDNA positivity

  Up to 5 years from enrollment

• Disease-specific recurrence

  At 3 years and 5 years.

• ctDNA positivity rate

  From randomization to 3 years and 5 years

Study Arms (2)

Observation

OTHER

Participants will be monitored by their study physician and will not receive treatment

Device: Signatera Genome ultra-sensitive ctDNA blood test

Vaginal Brachytherapy (VBT)

ACTIVE COMPARATOR

Participants will receive standard-of-care vaginal brachytherapy

Device: Signatera Genome ultra-sensitive ctDNA blood test

Interventions

Signatera Genome ultra-sensitive ctDNA blood test DEVICE

Signatera Genome is intended for use as a post-surgical risk stratification tool for patients with early-stage HIR endometrial cancer. The test is used to identify patients with no evidence of MRD following definitive surgery.

Observation; Vaginal Brachytherapy (VBT)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Signed and dated informed consent form (ICF) obtained prior to any trial-specific enrollment procedure.
• \. Patient is ≥ 18 years-old at the time of ICF signature. 3. Able to submit sufficient residual tissue obtained per standard of care procedures.
• HIR patients must meet all the following selection criteria to be eligible for the randomization cohort in the study. Eligibility will be assessed by the investigator:
• FIGO 2009 Stage I after hysterectomy and lymph node assessment by bilateral pelvic lymphadenectomy or SLND
• If para-aortic lymph nodes are not pathologically assessed, documentation of surgical assessment or imaging is recommended.
• Stage I patients with endometrioid histology:
• Age 70 years or older with one uterine risk factor,
• Age 50-69 years with two risk factors,
• Age 18 - 49 years with three risk factors.
• Uterine risk factors include:
• Grade 2 or 3 tumor.
• Outer half depth of invasion.
• Lymphovascular invasion. Note: peritoneal cytology must be negative if performed.
• Patients must meet all the following selection criteria to be eligible for the observation arms of the study. Eligibility will be assessed by the investigator following hysterectomy and lymph node assessment by bilateral pelvic and para-aortic lymphadenectomy or SLND:
• \. High risk cohort

You may not qualify if:

• Patients are not eligible for the study if they meet any of the following criteria, as assessed by the investigator:
• Undifferentiated or dedifferentiated histology
• Uterine sarcoma
• Prior pelvic radiation therapy
• Positive pelvic washings
• Pelvic lymph node assessment was not performed
• Isolated Tumor Cells (ITC) identified in the lymph node(s)
• Prior therapy for endometrial cancer (including hormonal therapy, chemotherapy, targeted therapy, immunotherapy)
• a. Contraceptives or other hormonal management for endometrial intraepithelial hyperplasia is allowed
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of active malignancy within the last five years.
• a. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.
• Patients with a history of serious comorbid illness or uncontrolled illnesses that would preclude protocol therapy.
• Patients with a history of myocardial infarction, unstable angina, or uncontrolled arrhythmia within 3 months from enrollment.
• Previous diagnosis of Crohn's disease or ulcerative colitis.
• Patient is currently receiving, or plans to receive, commercial ctDNA/MRD assay for disease monitoring, excluding Signatera. Patients must agree to forego testing with assays other than Signatera Genome upon enrollment until end of study.

Sponsors & Collaborators

• Natera, Inc.: lead

Study Sites (9)

University of Alabama at Birmingham Hospital

Birmingham, Alabama, 35294, United States

Location

University of California, San Diego

La Jolla, California, 92093, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

New York University

New York, New York, 10016, United States

Location

Atrium Health Levine Cancer

Charlotte, North Carolina, 28204, United States

Location

Duke University

Durham, North Carolina, 27708, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44106, United States

Location

Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Related Publications (16)

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  BACKGROUND

• Mahdi H, Elshaikh MA, DeBenardo R, Munkarah A, Isrow D, Singh S, Waggoner S, Ali-Fehmi R, Morris RT, Harding J, Moslemi-Kebria M. Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study. Gynecol Oncol. 2015 May;137(2):239-44. doi: 10.1016/j.ygyno.2015.01.544. Epub 2015 Jan 29.

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• Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC, van den Bergh AC, de Winter KA, Koper PC, Lybeert ML, Slot A, Lutgens LC, Stenfert Kroese MC, Beerman H, van Lent M; postoperative Radiation Therapy in Endometrial Carcinoma Trial. Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial. J Clin Oncol. 2004 Apr 1;22(7):1234-41. doi: 10.1200/JCO.2004.08.159.

  PMID: 15051771 BACKGROUND

• Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA, Powell MA, Hendrickson MR, Kapp DS, Chan JK. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer. 2006 Mar 13;94(5):642-6. doi: 10.1038/sj.bjc.6603012.

  PMID: 16495918 BACKGROUND

• Siegenthaler F, Lindemann K, Epstein E, Rau TT, Nastic D, Ghaderi M, Rydberg F, Mueller MD, Carlson J, Imboden S. Time to first recurrence, pattern of recurrence, and survival after recurrence in endometrial cancer according to the molecular classification. Gynecol Oncol. 2022 May;165(2):230-238. doi: 10.1016/j.ygyno.2022.02.024. Epub 2022 Mar 8.

  PMID: 35277281 BACKGROUND

• Feng W, Jia N, Jiao H, Chen J, Chen Y, Zhang Y, Zhu M, Zhu C, Shen L, Long W. Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer. J Transl Med. 2021 Feb 3;19(1):51. doi: 10.1186/s12967-021-02722-8.

  PMID: 33536036 BACKGROUND

• Makker V, MacKay H, Ray-Coquard I, Levine DA, Westin SN, Aoki D, Oaknin A. Endometrial cancer. Nat Rev Dis Primers. 2021 Dec 9;7(1):88. doi: 10.1038/s41572-021-00324-8.

  PMID: 34887451 BACKGROUND

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  PMID: 36139659 BACKGROUND

• Clarke MA, Devesa SS, Harvey SV, Wentzensen N. Hysterectomy-Corrected Uterine Corpus Cancer Incidence Trends and Differences in Relative Survival Reveal Racial Disparities and Rising Rates of Nonendometrioid Cancers. J Clin Oncol. 2019 Aug 1;37(22):1895-1908. doi: 10.1200/JCO.19.00151. Epub 2019 May 22.

  PMID: 31116674 BACKGROUND

• Giaquinto AN, Broaddus RR, Jemal A, Siegel RL. The Changing Landscape of Gynecologic Cancer Mortality in the United States. Obstet Gynecol. 2022 Mar 1;139(3):440-442. doi: 10.1097/AOG.0000000000004676.

  PMID: 35115431 BACKGROUND

• https://seer.cancer.gov/csr/1975_2018/

  BACKGROUND

• Sohaib SA, Houghton SL, Meroni R, Rockall AG, Blake P, Reznek RH. Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol. 2007 Jan;62(1):28-34; discussion 35-6. doi: 10.1016/j.crad.2006.06.015.

  PMID: 17145260 BACKGROUND

• Howlader N, N.A., Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds), SEER Cancer Statistics Review, 1975-2017. National Cancer Institute. Bethesda, MD

  BACKGROUND

• Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16.

  PMID: 39817679 BACKGROUND

• van den Heerik ASVM, Horeweg N, Creutzberg CL, Nout RA. Vaginal brachytherapy management of stage I and II endometrial cancer. Int J Gynecol Cancer. 2022 Mar;32(3):304-310. doi: 10.1136/ijgc-2021-002493.

  PMID: 35256416 BACKGROUND

• Kako TD, Kamal MZ, Dholakia J, Scalise CB, Arend RC. High-intermediate risk endometrial cancer: moving toward a molecularly based risk assessment profile. Int J Clin Oncol. 2022 Feb;27(2):323-331. doi: 10.1007/s10147-021-02089-2. Epub 2022 Jan 17.

  PMID: 35038071 BACKGROUND

MeSH Terms

Conditions

Endometrial Neoplasms

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Adam ElNaggar, MD

  Natera, Inc.

  STUDY DIRECTOR

Central Study Contacts

Brooke Cormane, MBS

CONTACT

844-778-4700; bcormane@natera.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Following the initial baseline test, providers in Arm A will be blinded to all subsequent ctDNA results unless ctDNA positive within the first 12 weeks in Arm A (in which case, the provider will be notified and TPC will be initiated). Providers treating participants in Arm B will remain blinded to all ctDNA results following the initial baseline test. Providers and patients enrolled in the early stage low-risk and high-risk cohorts will be blinded to all ctDNA results (post-operatively, during treatment, and during surveillance).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2025
• First Posted: January 14, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): May 1, 2034
• Study Completion (Estimated): May 1, 2034
• Last Updated: April 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)