STUDY02001740;22SCH740: Estradiol For ER+ Advanced Breast Cancer (ESTHER) (ESTHER)

Phase II Study of Estradiol Therapy to Target ER-Mutant and ER-Wild-Type ER+ Metastatic or Advanced Breast Cancer

Determine whether subjects harboring ESR1-mutant/amplified breast cancer have a higher rate of clinical benefit from 17b-estradiol therapy than subjects with ESR1-wild-type breast cancer

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Estradiol

Detailed Description

Patients with endocrine-resistant breast cancer are eligible. Treatment Phase: Patients will be treated with 17b-estradiol until disease progression. At this point, the patient will end protocol therapy. Clinical benefit, progression-free survival, objective response, tumor metabolic response, and toxicity will be determined. Observational Phase (optional): After disease progression on 17b-estradiol, patients will be treated at their oncologist's discretion. Clinical benefit, progression-free survival, and objective response will be measured during this line of treatment of physician's choice until another instance of disease progression. In consented subjects who undergo a clinically indicated tumor biopsy of recurrent or metastatic disease prior to the start of 17b-estradiol treatment, when feasible, acquisition of additional tumor tissue is requested for research purposes. Optional: patients will be asked to provide tumor tissue via a research biopsy on Day 3-4 of 17b-estradiol treatment. Archived tumor tissue and clinical-grade tumor and plasma DNA/RNA sequencing results will be used for research purposes. Blood samples will be obtained at baseline, on Day 3-4 of 17b-estradiol therapy (optional), and upon disease progression on 17b-estradiol. Plasma and buffy coat will be extracted and frozen. Tumor tissue and plasma specimens will be analyzed to identify molecular biomarkers predictive of sensitivity/resistance to 17b-estradiol therapy

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Research Nurse; Phone Number: 1-800-639-6918; Email: Cancer.Research.Nurse@dartmouth.edu

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Post-menopausal women with ER+ breast cancer.
• Metastatic or locoregional recurrence not amenable to treatment with curative
• intent.
• Received ≥1 prior line of endocrine-based therapy (e.g., including tamoxifen, aromatase inhibitors, fulvestrant, or combinations) in the advanced/metastatic setting

Exclusion Criteria:

• During the study Treatment Phase with 17b-estradiol, no concurrent anti-cancer therapies are allowed with the following exceptions:

  • Exception: Trastuzumab is allowed for the treatment of subjects with a history of HER2+ disease, and will be used at the physician's discretion.
  • Exception: Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
• Any investigational cancer therapy in the last 3 weeks.
• Known CNS disease, unless clinically stable for ≥ 3 months.

• History of any of the following:

  • Deep venous thrombosis.
  • Pulmonary embolism.
  • Stroke.
  • Acute myocardial infarction.
  • Congestive heart failure.
  • Previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥30%.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Treatment Arm; Treatment Phase: Patients will be treated with 17b-estradiol until disease progression. At this point, the patient will end protocol therapy	Drug: Estradiol; Estradiol is a therapeutic option for the treatment of advanced ER+ breast cancer; Other Names: Estrace

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate	The clinical benefit rate (complete responses + partial responses + stable disease at 24 weeks) will be ascertained and compared between subjects treated with 17b-estradiol harboring amplified/mutant ESR1 and wild-type ESR1.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	The objective response rate (complete + partial responses) to the first 8 weeks of treatment with 17b-estradiol will be ascertained and compared between subjects harboring amplified/mutant ESR1 and wild-type ESR1.	8 weeks
Progression-free survival	Progression-free survival with 17b-estradiol treatment will be ascertained and compared between subjects harboring amplified/mutant ESR1 and wild-type ESR1.	12 months
Tumor Metabolic response	Tumor metabolic response will be defined as the best response at any time point per PERCIST. The metabolic response rate (complete + partial metabolic response) will be ascertained and compared between subjects treated with 17b-estradiol harboring amplified/mutant ESR1 and wild-type ESR1.	12 months
Adverse event profiles	The number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be collected	12 months

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Muhammad Azfal, MD, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2023
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: January 28, 2023
• First Submitted That Met QC Criteria: January 28, 2023
• First Posted (Actual): February 8, 2023

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic; Locally advanced; Estrogen therapy; Estradiol therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Breast Neoplasms; Neoplasm Metastasis; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Estradiol
• Other Study ID Numbers: STUDY02001740; NCI-2023-05453 (Other Identifier: National Cancer Institute)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No