Signatera Assessment in Early-Stage Endometrial Cancer (SIGNAL-EMC 101)

April 21, 2026 updated by: Natera, Inc.

Circulating Tumor DNA Assessment in Early-Stage Endometrial Cancer (SIGNAL-EMC 101)

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

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This includes a randomized, multi-center, non-inferiority trial for a biomarker-defined subgroup, alongside two parallel, non-randomized exploratory cohorts. The study utilizes a biomarker-stratified design to formally test a treatment de-escalation strategy in patients with HIR endometrial cancer.

Following surgery, patients in the HIR cohort will be stratified based on post-operative circulating tumor DNA (ctDNA) status, as determined by the Signatera Genome assay. ctDNA-negative HIR Patients, based on the first valid post-operative ctDNA result within the baseline window, will be randomized (1:1) to either:

  • Arm A: Observation unless ctDNA positivity within baseline window (<12 weeks), with serial ctDNA monitoring.
  • Arm B: Vaginal brachytherapy (VBT) with serial ctDNA monitoring.

Following the initial baseline test, providers will be blinded to subsequent ctDNA results unless ctDNA positive within the first 12 weeks in Arm A [in which case, the provider will be notified and treatment of physician's choice (TPC) will be initiated. Initiation of TPC following ctDNA conversion is considered part of the ctDNA-guided treatment strategy, not a protocol deviation or cross-over, and such patients remain in the intent-to-treat population in Arm A]. Providers treating patients in Arm B will remain blinded to all ctDNA results after randomization. Post-operative ctDNA-Positive HIR patients will not be randomized and will continue serial testing while receiving TPC, which may include observation, radiation and/or chemotherapy. Providers and patients will be unblinded to the initial ctDNA result and blinded to ctDNA results thereafter.

The study will also include early stage low-risk (LR) and high-risk (HR) cohorts. Patients in these cohorts will not be randomized. They will continue serial ctDNA testing while receiving TPC, which may include observation, radiation and/or chemotherapy, and during surveillance. Providers and patients will be blinded to ctDNA results during the post-operative, TPC and surveillance period.

Study Type

Interventional

Enrollment (Estimated)

1010

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama At Birmingham Hospital
        • Principal Investigator:
          • Michael Toboni, MD
    • California
      • La Jolla, California, United States, 92093
        • University of California, San Diego
        • Principal Investigator:
          • Ramez Eskander, MD
      • Los Angeles, California, United States, 90095
        • University of California, Los Angeles
        • Principal Investigator:
          • Dana Chase, MD
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota
        • Principal Investigator:
          • Melissa Geller, MD
    • New York
      • New York, New York, United States, 10016
        • New York University
        • Principal Investigator:
          • Bhavana Pothuri, MD
    • North Carolina
      • Charlotte, North Carolina, United States, 28204
        • Atrium Health Levine Cancer
        • Principal Investigator:
          • Allison Puechl, MD
      • Durham, North Carolina, United States, 27708
        • Duke University
        • Principal Investigator:
          • Angeles Secord, MD
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Cleveland Clinic
        • Principal Investigator:
          • Kevin Elias, MD
      • Columbus, Ohio, United States, 43210
        • Ohio State University Wexner Medical Center
        • Principal Investigator:
          • Floor Backes, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

General inclusion criteria includes the following selection criteria to be eligible for inclusion in any aspect of the study. Eligibility will be assessed by the investigator:

1. Signed and dated informed consent form (ICF) obtained prior to any trial-specific enrollment procedure.

2. 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:

  1. FIGO 2009 Stage I after hysterectomy and lymph node assessment by bilateral pelvic lymphadenectomy or SLND

    1. If para-aortic lymph nodes are not pathologically assessed, documentation of surgical assessment or imaging is recommended.

  2. Stage I patients with endometrioid histology:

    1. Age 70 years or older with one uterine risk factor,
    2. Age 50-69 years with two risk factors,
    3. 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:

1. High risk cohort

a. FIGO 2009 Stage I with high risk histology i. Defined as serous, clear cell, carcinosarcoma, or mixed histology.

  1. Negative peritoneal cytology, where performed (recommended)
  2. If para-aortic lymph nodes are not pathologically assessed, imaging is required b. FIGO 2009 Stage II Endometrioid

2. Low risk cohort

a. FIGO 2009 Stage I patients at low risk of recurrence i. Endometriod histology ii. Absent uterine risk factors, or present but insufficient to meet HIR criteria

Exclusion Criteria:

Patients are not eligible for the study if they meet any of the following criteria, as assessed by the investigator:

  1. Undifferentiated or dedifferentiated histology
  2. Uterine sarcoma
  3. Prior pelvic radiation therapy
  4. Positive pelvic washings
  5. Pelvic lymph node assessment was not performed
  6. Isolated Tumor Cells (ITC) identified in the lymph node(s)

  7. Prior therapy for endometrial cancer (including hormonal therapy, chemotherapy, targeted therapy, immunotherapy)

    a. Contraceptives or other hormonal management for endometrial intraepithelial hyperplasia is allowed

  8. 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.

  9. Patients with a history of serious comorbid illness or uncontrolled illnesses that would preclude protocol therapy.
  10. Patients with a history of myocardial infarction, unstable angina, or uncontrolled arrhythmia within 3 months from enrollment.
  11. Previous diagnosis of Crohn's disease or ulcerative colitis.
  12. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Observation
Participants will be monitored by their study physician and will not receive treatment
Device: Signatera Genome ultra-sensitive ctDNA blood test
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.
Active Comparator: Vaginal Brachytherapy (VBT)
Participants will receive standard-of-care vaginal brachytherapy
Device: Signatera Genome ultra-sensitive ctDNA blood test
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recurrence Free Survival (RFS)
Time Frame: 3 years from randomization to the first occurrence of disease recurrence or death from any cause, whichever occurs first
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survial
Time Frame: From enrollment to Year 3 and enrollment to Year 5
Comparison of overall survival (OS) among all high-intermediate risk (HIR) patients and recurrence free survival (RFS) across treatment groups and assess whether ctDNA-guided de-escalation group is non-inferior to adjuvant VBT.
From enrollment to Year 3 and enrollment to Year 5
ctDNA Clearance Rate
Time Frame: From enrollment until first surveillance visit at 12 weeks
Estimate the ctDNA clearance rate among high-intermediate risk ctDNA positive participants.
From enrollment until first surveillance visit at 12 weeks
Clinicopathologic and Molecular Risk Factors
Time Frame: Up to 5 years from enrollment
Assess the primary and secondary objectives by clinicopathologic and molecular (e.g. POLE, MMR-D, p53 aberrant, p53 wild type) risk factors, and ethnic/racial groups among high-intermediate risk patients.
Up to 5 years from enrollment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lead time of ctDNA positivity
Time Frame: Up to 5 years from enrollment
Examine differences in lead time of ctDNA positivity relative to clinical or radiologic diagnosis of recurrence across different ctDNA dynamic groups (e.g. clearance, persistent negative) among LR, HIR, and HR patients.
Up to 5 years from enrollment
Disease-specific recurrence
Time Frame: At 3 years and 5 years.
Determine disease-specific recurrence among high-intermediate risk patients.
At 3 years and 5 years.
ctDNA positivity rate
Time Frame: From randomization to 3 years and 5 years
Assess ctDNA positivity rate, defined as proportion of patients, among all HIR, HR, and LR patients with evaluable ctDNA results
From randomization to 3 years and 5 years
ctDNA negativity rate
Time Frame: From randomization to 3 years and 5 years
ctDNA negativity rate, defined as proportion of patients with a negative ctDNA, among all HIR, HR, and LR patients with evaluable ctDNA results.
From randomization to 3 years and 5 years
ctDNA clearance rate
Time Frame: From enrollment up to 5 years
Assess the ctDNA clearance rate of ctDNA from HIR, HR, and LR participants.
From enrollment up to 5 years
ctDNA negative persistence rate
Time Frame: From enrollment to end of treatment and up to 5 years.
Assess proportion of HIR, HR, and LR participants who remain ctDNA-negative throughout the surveillance period among participants who were ctDNA-negative post-operatively or post-adjuvant treatment.
From enrollment to end of treatment and up to 5 years.
Mean Tumor Molecules (MTM)
Time Frame: From enrollment to up to 5 years
Assess mean tumor molecules (MTM) presence change over time in HIR, HR, and LR participants.
From enrollment to up to 5 years
Variant Allele Frequencies (VAF)
Time Frame: From enrollment up to 5 years
Assess variant allele frequencies (VAF) changes over time in HIR, HR, and LR participants.
From enrollment up to 5 years
Cost-effectiveness of ctDNA guided care
Time Frame: Up to 5 years from enrollment
Compare the ctDNA cost for High-Risk Intermediate endometrial cancer participants who were randomized to the observation cohort to those that received standard of care (VBT) treatment
Up to 5 years from enrollment
Quality of Life Outcomes
Time Frame: Up to 5 years from enrollment
Compare Quality of Life (QoL) outcomes between the Observation and Vaginal Brachytherapy (VBT) treatment arms among HIR patients, utilizing the Functional Assessment of Cancer Therapy - Endocrine Symptoms Version 4 (FACT-ES) patient-reported outcome (PRO).
Up to 5 years from enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Natera, Inc.

Investigators

  • Study Director: Adam ElNaggar, MD, Natera, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

May 1, 2034

Study Completion (Estimated)

May 1, 2034

Study Registration Dates

First Submitted

December 30, 2025

First Submitted That Met QC Criteria

January 13, 2026

First Posted (Actual)

January 14, 2026

Study Record Updates

Last Update Posted (Actual)

April 22, 2026

Last Update Submitted That Met QC Criteria

April 21, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 25-102-NCP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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