Signatera-Guided CDK4/6 Inhibitor Therapy in Breast Cancer

Официальное название

SIgnatera-Guided Initiation of Adjuvant CDK4/6 Inhibitor in Intermediate Risk HR+ HER2- Breast Cancer

Обзор

The purpose of this study is to evaluate the efficacy and safety of ctDNA-guided initiation of CDK4/6 inhibitor therapy using the Signatera™ Designed on Genome test (referred to as "Signatera Genome") in participants with intermediate-risk HR+/HER2- early-stage breast cancer. Based on ctDNA test results, participants will either start CDK4/6 inhibitor therapy in addition to hormone therapy or continue hormone therapy with ongoing ctDNA surveillance. This study will compare outcomes to historical controls from the NataLEE trial to determine whether ctDNA-guided timing maintains efficacy while reducing unnecessary treatment. Participants will be followed for up to 9 years with regular blood draws, hormone therapy, imaging as needed, and quality-of-life assessments.

Подробное описание

Participants with intermediate-risk, early-stage HR+/HER2- breast cancer will be enrolled in a prospective, single-arm, multicenter phase II study. Circulating tumor DNA (ctDNA) surveillance will be performed using the Signater Genome assay, which is customized for each participant from archived tumor and matched normal DNA to detect up to 64 tumor-specific variants in plasma.

Participants who are ctDNA positive at baseline will start CDK4/6 inhibitor therapy along with hormone therapy. Those who are ctDNA negative will continue hormone therapy with ctDNA testing every three months. If ctDNA becomes positive during surveillance, participants will first undergo staging to rule out distant disease before beginning CDK4/6 inhibitor therapy in addition to hormone therapy.

All participants will be followed for up to nine years to assess cancer outcomes. Four-year outcomes will be compared to historical controls from the NataLEE trial to evaluate whether ctDNA-guided timing maintains efficacy while reducing unnecessary treatment.

Вмешательства

• Устройство ctDNA-Guided Treatment Strategy
  Circulating tumor DNA testing using Signatera Genome assay is performed every 3 months for up to 4 years to guide timing of CDK4/6 inhibitor initiation. Participants with positive ctDNA results initiate CDK4/6 inhibitor therapy (ribociclib or abemaciclib) plus standard endocrine therapy for a minimum of 2 years. Participants with negative ctDNA results continue endocrine therapy alone with ongoing surveillance. CDK4/6 inhibitor selection and endocrine therapy regimen per the physician's choice f

Первичные конечные точки

• Invasive Disease-Free Survival [Срок оценки: From the date of surgery up to 9 years]

Критерии участия

Критерии включения

• Signed and dated Informed Consent Form (ICF) obtained prior to any trial-specific screening procedure.
• Patient is ≥ 18 years-old at the time of ICF signature.
• Patient is female with known menopausal status at the time of initiation of adjuvant endocrine therapy (ET), or male.
• Patient with histologically confirmed unilateral and unifocal primary invasive adenocarcinoma of the breast prior to initiating adjuvant chemotherapy, if indicated, or within 6 months of initiating adjuvant endocrine therapy if chemotherapy is not indicated. Patients who receive neoadjuvant endocrine therapy or chemotherapy are allowed to enroll.
• Patient has breast cancer that is positive for ER and/or PR according to the local laboratory as determined on the most recently analyzed tissue sample.
• Patient has HER2-negative breast cancer defined as a negative in situ hybridization test (FISH, CISH, or SISH) or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (ISH) test is required to confirm the HER2-negative status.
• Patient has available archival tumor tissue from the diagnostic biopsy or surgical specimen, for submission to a central laboratory for Signatera testing (unless Signatera Genome clinical testing has already been performed).
• Patient after surgical resection where tumor was removed completely (i.e., negative microscopic margins on final pathology) and have Anatomic Stage II that is either:

• N1 or,
• If N0, T2 or T3 with G2-3 and/or Ki67≥20% (testing for Ki67 not mandatory), excluding G1.

Notes:

• Patients who received neoadjuvant treatment must meet the criteria for stage, grade, Ki67 in any presurgical staging/sample and/or in the surgical specimen.
• Categorization into the AJCC 8th edition Anatomic Stage Groups requires determination of the T, N and M categories. ALND can be omitted.
• Patient has no contraindication to adjuvant ET and is planned to be treated with ET for 5 years (since enrollment date) or more.
• Provider and patient must be agreeable to initiate CDK4/6 inhibitors only upon ctDNA detection.
• Patient may have received up to 6 months of standard adjuvant ET at the time of enrollment and any amount of neoadjuvant endocrine therapy.
• Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Patient must not have a clinical contraindication to ribociclib or abemaciclib.
• Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
• Women of childbearing potential (CBP) must have a confirmed negative serum pregnancy test within 14 days prior to enrollment.
• Women of reproductive potential should be advised of the potential risk of CDK4/6 inhibitors to a fetus, and use effective contraception during CDK 4/6 inhibitor therapy.

Критерии исключения

• Patient has had prior exposure to a CDK4/6 inhibitor.
• Patient is concurrently using hormone replacement therapy.
• Patient with a known contraindication or hypersensitivity to ribociclib or abemaciclib as per the FDA indication label.
• Patients with a multicentric and/or multifocal and synchronous contralateral breast cancer are ineligible.
• Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
• Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 5 years before ICF signature. Note: Patients with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to enrollment.
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic antibacterial therapy, etc.) or limit life expectancy to ≤5 years.
• Patient participated in another interventional study and received treatment with an investigational product (or used an investigational device) within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 39 центров

• University of Alabama at Birmingham — Birmingham
• Mayo Clinic Arizona — Phoenix
• Honor Health Research Institute — Scottsdale
• University of Arizona Cancer Center — Tucson
• Adventist Health/AIS Cancer Center — Bakersfield
• Marin Cancer Care — Greenbrae
• Loma Linda University — Loma Linda
• UCLA David Geffen School of Medicine — Santa Monica
• … и ещё 31 центр

Публикации

• Cohen SA, Liu MC, Aleshin A. Practical recommendations for using ctDNA in clinical decision making. Nature. 2023 Jul;619(7969):259-268. doi: 10.1038/s41586-023-06225-y. Epub 2023 Jul 12. PMID 37438589
• Kanjanapan Y, Anderson W, Smith M, Green J, Chalker E, Craft P. Real-World Analysis of Breast Cancer Patients Qualifying for Adjuvant CDK4/6 Inhibitors. Clin Breast Cancer. 2025 Feb;25(2):e159-e169.e2. doi: 10.1016/j.clbc.2024.08.022. Epub 2024 Aug 29. PMID 39294027
• Magbanua MJM, Brown Swigart L, Ahmed Z, Sayaman RW, Renner D, Kalashnikova E, Hirst GL, Yau C, Wolf DM, Li W, Delson AL, Asare S, Liu MC, Albain K, Chien AJ, Forero-Torres A, Isaacs C, Nanda R, Tripathy D, Rodriguez A, Sethi H, Aleshin A, Rabinowitz M, Perlmutter J, Symmans WF, Yee D, Hylton NM, Esserman LJ, DeMichele AM, Rugo HS, van 't Veer LJ. Clinical significance and biology of circulating tu PMID 37146605
• Cutts R, Ulrich L, Beaney M, Robert M, Coakley M, Bunce C, Crestani GW, Hrebien S, Kalashnikova E, Wu HT, Dashner S, Sethi H, Aleshin A, Liu M, Ring A, Okines A, Smith IE, Barry P, Turner NC, Garcia-Murillas I. Association of post-operative ctDNA detection with outcomes of patients with early breast cancers. ESMO Open. 2024 Sep;9(9):103687. doi: 10.1016/j.esmoop.2024.103687. Epub 2024 Aug 30. PMID 39216186
• Natarajan A, Tolaney SM. Is adjuvant ribociclib ready for prime time? Ann Oncol. 2024 Dec;35(12):1200-1201. doi: 10.1016/j.annonc.2024.08.2341. Epub 2024 Sep 4. No abstract available. PMID 39241962
• Johnston SRD, Harbeck N, Toi M, Martin M, O'Shaughnessy J, Rastogi P. Reply to K. Hashimoto and A. Shimomura. J Clin Oncol. 2021 May 1;39(13):1507-1508. doi: 10.1200/JCO.20.03477. Epub 2021 Feb 25. No abstract available. PMID 33630658
• Kay C, Martinez-Perez C, Dixon JM, Turnbull AK. The Role of Nodes and Nodal Assessment in Diagnosis, Treatment and Prediction in ER+, Node-Positive Breast Cancer. J Pers Med. 2023 Oct 8;13(10):1476. doi: 10.3390/jpm13101476. PMID 37888087
• Nelson DR, Brown J, Morikawa A, Method M. Breast cancer-specific mortality in early breast cancer as defined by high-risk clinical and pathologic characteristics. PLoS One. 2022 Feb 25;17(2):e0264637. doi: 10.1371/journal.pone.0264637. eCollection 2022. PMID 35213669

Идентификаторы

NCT: NCT07214532 · 25-085-NCP

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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