ERADICATE: A Phase Ib/II Study of Elacestrant Plus Trastuzumab Deruxtecan in Patients With CDK4/6 Inhibitor and Endocrine-resistant HR+/HER2-low or HER2-ultralow Metastatic Breast Cancer

NCT07198724 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 25-437
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to evaluate the safety and efficacy of elacestrant in combination with trastuzumab deruxtecan (T-DXd) in participants with hormone receptor-positive (HR+), HER2-low or HER2-ultralow, metastatic breast cancer that is resistant to prior CDK4/6 inhibitor and endocrine therapy. The names of the study drugs involved in this study are:

• Elacestrant (a type of selective estrogen receptor degrader)
• Trastuzumab deruxtecan (a type of standard of care antibody drug conjugate)

Conditions

HER2 Low Breast Carcinoma; HER2-negative Breast Cancer; Breast Cancer Female; Breast Cancer; Metastatic Breast Cancer

Keywords

Metastatic Breast Cancer; HER2 Low Breast Carcinoma; HER2-negative Breast Cancer; Breast Cancer; Breast Cancer Female; HR+/HER2-low Breast Cancer; HR+/HER2-ultralow Breast Cancer; Endocrine-resistant Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Recommended phase II dose (RP2D)

  The RP2D is defined as the dose at which ≤ 3 out of 12 participants experience Dose Limiting Toxicities (DLT) during the first treatment cycle.

  Assessed at the end of the first treatment cycle, Day 21.

• Objective Response Rate (ORR)

  ORR per RECIST 1.1 is defined as the percentage of participants with confirmed complete or partial response as the best overall response.

  assessed for response every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 24 months

Secondary Outcomes (9)

• ORR in Participants with ESR1-mutant endocrine- and CDK4/6 inhibitor-resistant HR+/HER2-low or HER2-ultralow metastatic breast cancer

  assessed for response every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 24 months

• Clinical Benefit Rate (CBR)

  assessed for response every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 24 months

• CBR in Participants with ESR1-mutant endocrine- and CDK 4/6 inhibitor-resistant HR+/HER2-low of HER2-ultralow metastatic cancer

  assessed for response every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 24 months

• Median progression-free survival (PFS)

  assessed for response/progression every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 36 months

• Median PFS in Participants with ESR1-mutant endocrine- and CDK4/6 inhibitor-resistant HR+/HER2-low or HER2-ultralow metastatic breast cancer

  assessed for response/progression every 9 weeks (3 cycles) +/- 7 days for the first 27 weeks, then every 12 weeks +/- 7 days, and at end of treatment or start of new anticancer therapy, or up to approximately 36 months

Study Arms (2)

Phase 1b: Elacestrant + Trastuzumab Deruxtecan

EXPERIMENTAL

Up to 28 participants will be enrolled to determine the recommended phase 2 dosage of Elacestrant and will complete the following: * Baseline visit * Cycle 1 (21 day cycle) * Days 1 through 21: Predetermined dose of Elacestrant 1x daily. * Day 1: Predetermined dose of Trastuzumab Deruxtecan 1x daily. * Cycle 2 through End of Treatment (21 day cycle): * Imaging every 9 weeks until Cycle 9, then every 12 weeks * Day 1: tumor biopsy * Days 1 through 21: Predetermined dose of Elacestrant 1x daily. * Day 1: Predetermined dose of Trastuzumab Deruxtecan 1x daily. * End of Treatment visit with imaging * Follow up visits every 6 months * If 3 or less out of 12 participants experience a dose-limiting toxicity (DLT), the recommended Phase II dose of Elacestrant will be that dose level. If there are 4 or more DLTs, Elacestrant dosage will de-escalate and 12 more participants will be enrolled.

Drug: Elacestrant; Drug: Trastuzumab Deruxtecan

Phase 2: Elacestrant + Trastuzumab Deruxtecan

EXPERIMENTAL

37 participants will complete the following: * Baseline visit -Cycle 1 (21 day cycle) * Days 1 through 21: Predetermined dose of Elacestrant 1x daily. * Day 1: Predetermined dose of Trastuzumab Deruxtecan 1x daily. -Cycle 2 through End of Treatment (21 day cycle): * Imaging every 9 weeks until Cycle 9, then every 12 weeks * Day 1: tumor biopsy * Days 1 through 21: Predetermined dose of Elacestrant 1x daily. * Day 1: Predetermined dose of Trastuzumab Deruxtecan 1x daily. * End of Treatment visit with imaging * Follow up visits every 6 months

Drug: Elacestrant; Drug: Trastuzumab Deruxtecan

Interventions

Trastuzumab Deruxtecan DRUG

HER2-directed antibody-drug conjugate, vial, via intravenous (into the vein) infusion per standard of care

Also known as: Fam-Trastuzumab, ENHERTU, DS-8201a, T-DXd

Phase 1b: Elacestrant + Trastuzumab Deruxtecan; Phase 2: Elacestrant + Trastuzumab Deruxtecan

Elacestrant DRUG

Selective estrogen receptor degrader (SERD), film-coated tablet, taken orally per protocol.

Also known as: Elacestrant dihydrochloride, RAD1901

Phase 1b: Elacestrant + Trastuzumab Deruxtecan; Phase 2: Elacestrant + Trastuzumab Deruxtecan

Eligibility Criteria

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

You may qualify if:

• Participants must have a histologically or cytologically confirmed diagnosis of HR+/HER2-low metastatic or unresectable locally advanced breast cancer, defined as ER ≥ 10%, any PR in the most recent sample and HER2-low (IHC 1+ or IHC 2+ and ISH non-amplified) or HER2-ultralow (IHC 0 and any membranous staining on any prior sample). Cutoff values for positive/negative HER2 staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.76 Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiographic evaluation.
• Participants must have had prior CDK4/6 inhibitor and either:
• Disease progression on or within 12 months of endocrine therapy plus a CDK4/6 inhibitor in the adjuvant setting
• One previous line of endocrine therapy in metastatic setting if disease progression within 6 months of first-line CDK4/6 plus endocrine treatment for metastatic disease or disease recurrence within 24 months after initiation of adjuvant endocrine therapy
• Two previous lines of endocrine therapy in the metastatic with or without a targeted therapy (such as but not limited to CDK4/6, mTOR, or PI3K inhibitors) administered for the treatment of metastatic disease.
• Of note with regards to the 2 lines of previous endocrine therapy requirement:- Disease recurrence while on the first 24 months of adjuvant endocrine therapy will be considered a line of therapy; these patients will only require 1 line of endocrine therapy in the metastatic setting.
• Single-agent PARP inhibitor therapy is not considered a line of endocrine therapy but is allowed.
• Changes in dosing schedules, or discontinuations/restarting of the same drugs of the addition of a targeted therapy to an endocrine therapy without progression (e.g., adding a CDK4/6 inhibitor to a current aromatase inhibitor regimen) will not be considered separate lines of therapy.
• Participants may have not received prior chemotherapy or ADC in the metastatic setting.
• Participants must have measurable disease per RECIST 1.1 criteria. See Section 11 for the definition of measurable disease. Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.
• Participants must have known ESR1 mutation status in tumor or ctDNA within 6 months of enrollment to the trial.
• Women or men age ≥18 years are eligible.
• ECOG performance status ≤ 2.
• Participants must meet the following organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,500/µL

You may not qualify if:

• Prior treatment with an antibody-drug conjugate in any setting.
• Prior treatment with an oral novel estrogen receptor degrader or modulator in the metastatic setting (SERD, SERM, PROTAC, or CERAN). Prior fulvestrant is allowed. A washout period of 7 days is required for any endocrine or targeted therapy.
• Patients with known brain metastases that are symptomatic or that require therapy for symptom control are not eligible. Patients with stable or asymptomatic brain metastases are allowed. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 4 weeks before day 1 of study therapy will be excluded.
• Receipt of any other investigational compound or device within 2 weeks of the first dose of treatment in this study.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to elacestrant or T-DXd.
• History of (non-infectious) pneumonitis that required steroids or current ILD by imaging at screening.
• Patients who are pregnant or breastfeeding, or who expect to become pregnant within the projected duration of the study (starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for those who have not).
• Patients with a known history of active tuberculosis.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic therapy, clinically significant cardiovascular disease including: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, uncontrolled diabetes mellitus, gastrointestinal disorders potentially affecting the absorption of elacestrant, inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or total gastric resection, or psychiatric illness/social situations that would limit compliance with study requirements. Active hepatitis B or active hepatitis C infection. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
• Patients with a history of different malignancy are ineligible, except for those who have been disease-free for at least three years and are deemed by the investigator to be at low risk for recurrence of the prior malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last six months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV

Sponsors & Collaborators

• Sarah Sammons, MD: lead
• Stemline Therapeutics, Inc.: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

elacestrant; RAD1901; trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Sarah Sammons, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sarah Sammons, MD

CONTACT

617-362-3800; Sarah_Sammons@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: September 22, 2025
• First Posted: September 30, 2025
• Study Start: November 17, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2038
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)