Signatera Assessment in Early-Stage Endometrial Cancer

Official title

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

Overview

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

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.

Interventions

• 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.

Primary outcome measures

• 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]

Secondary outcome measures (3)

• Overall Survial [Time frame: From enrollment to Year 3 and enrollment to Year 5]
• ctDNA Clearance Rate [Time frame: From enrollment until first surveillance visit at 12 weeks]
• Clinicopathologic and Molecular Risk Factors [Time frame: Up to 5 years from enrollment]

Eligibility criteria

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:

• 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:

1\. High risk cohort

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

• Negative peritoneal cytology, where performed (recommended)
• 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:

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 12 centers

• University of Alabama at Birmingham Hospital — Birmingham
• University of California, San Diego — La Jolla
• University of California, Los Angeles — Los Angeles
• University of Miami — Miami
• University of Chicago — Chicago
• University of Minnesota — Minneapolis
• New York University — New York
• Atrium Health Levine Cancer — Charlotte
• … and 4 more centers

Publications

• Firth, D. (1993). Bias reduction of maximum likelihood estimates. Biometrika, 80(1), 27-38
• 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. PMID 25641568
• 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 PMID 15051771
• 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
• 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
• 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
• 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
• Kalampokas E, Giannis G, Kalampokas T, Papathanasiou AA, Mitsopoulou D, Tsironi E, Triantafyllidou O, Gurumurthy M, Parkin DE, Cairns M, Vlahos NF. Current Approaches to the Management of Patients with Endometrial Cancer. Cancers (Basel). 2022 Sep 16;14(18):4500. doi: 10.3390/cancers14184500. PMID 36139659

Identifiers

NCT: NCT07339384 · 25-102-NCP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗