Study of Abemaciclib and Elacestrant in Patients With Brain Metastasis Due to ER+/HER-2- Breast Cancer

Phase 1

Recruiting

• Conditions: Neoplasms by Site; Neoplasms; Brain Diseases; Brain Neoplasms; Central Nervous System Neoplasms; Central Nervous System Diseases; Breast Neoplasms; Breast Diseases
• Interventions: Drug: Elacestrant; Drug: Abemaciclib

• Registration Number: NCT05386108
• Lead Sponsor: Stemline Therapeutics, Inc.

Brief Summary

This is a multi-site, global, open-label study that includes a phase 1b evaluation of elacestrant in combination with abemaciclib in women and men with brain metastases from estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER-2) negative breast cancer. Phase 1b was designed to select the recommended phase 2 dose and is followed by an ongoing phase 2 evaluation of elacestrant in combination with abemaciclib in patients with active brain metastases from ER-positive, HER-2 negative breast cancer.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-05-16
• Study First Submitted QC: 2022-05-18
• Study First Posted: 2022-05-23
• Study Start: 2022-08-31
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-06
• Last Update Posted: 2025-05-07
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 68

Inclusion Criteria

1. Patient has the signed informed consent form before any study-related activities according to local guidelines.

2. Women or men aged ≥18 years, at the time of informed consent signature.

   • Female patients may be either postmenopausal or pre/perimenopausal. Postmenopausal status is defined by:

     1. Age ≥60 years
     2. Age <60 years and amenorrhea for 12 or more months without an alternative cause) and follicle stimulating hormone and estradiol in postmenopausal ranges per local reference ranges
     3. Documentation of prior bilateral oophorectomy, at least 1 month before first dose of trial therapy).

3. Patient must have ER-positive, HER-2 negative tumor status as confirmed by local laboratory testing in the following manner:

   • Documentation of ER positive tumor with ≥ 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 American Society for Clinical Oncology (ASCO) recommendations for ER testing, with or without progesterone receptor (PGR) positivity
   • HER-2 negative tumor with an IHC result of 0 or 1+ for cellular membrane protein expression or an in situ hybridization negative result as defined in the 2013 or 2018 ASCO recommendations for HER-2 testing

4. In Phase 2, patients must have at least one active and measurable brain metastasis per RECIST version 1.1.

   • Any of the following qualifies brain metastases as active:

     1. Newly diagnosed brain metastasis in patients who never received prior central nervous system (CNS)-directed therapy.
     2. Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy.
     3. Brain metastases that are clearly progressing in an area that has previously been subjected to CNS-directed therapy.

   • For lesions, including brain metastases, to qualify as measurable, and possibly be selected as target lesions, per RECIST version 1.1 (Appendix C), the longest diameter must be ≥10 mm by CT or MRI).

   • In Phase 1b, the presence of brain metastases is allowed but not required for eligibility, in this case, at least 1 measurable lesion outside the brain is required.

5. Patients receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 7 days prior to baseline and not receiving doses higher than 4 mg of dexamethasone per day or equivalent.

6. Any neurological symptoms of brain metastases must be stable for at least 2 weeks before starting trial therapy. Fluctuations of the previously known symptoms deemed to be due to clinical intercurrent processes (e.g., electrolytes alterations, fever) are admissible if fully resolved before the first dose of study drugs.

7. Patient prior therapy received in the metastatic setting includes:

   • At least one endocrine therapy
   • Up to two chemotherapy regimens
   • Up to two prior CDK 4/6 inhibitors, not including abemaciclib Note 1: Toxicity from prior therapy must be resolved to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2).

8. Patient has documented intra- and/or extra-cranial radiological progression or recurrence while on or after the most recent therapy.

9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

10. Patient has adequate bone marrow and organ function, as defined by the following laboratory values:

    1. Absolute neutrophil count (ANC) ≥1.5 × 109/L

    2. Platelets ≥100 × 109/L

    3. Hemoglobin ≥9.0 g/dL

    4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE Grade ≤1 (if screening assessments are abnormal, these assessments may be repeated up to 2 times; subjects may receive appropriate supplementation or treatment prior to reassessment)

    5. Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/min

    6. Serum albumin ≥3.0 g/dL (≥30 g/L)

    7. Liver function tests:

       In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the patient has liver metastases, ALT and AST ≤5 × ULN.

    8. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

11. The patient is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria

1. Immediate CNS-specific treatment is likely to be required, per the treating physician's assessment.

2. Patient has imminent organ failure and/or visceral crisis.

3. Patient has leptomeningeal metastases, defined as having positive CSF cytology or unequivocal radiologic and clinical evidence of leptomeningeal involvement.

4. Breast cancer treatment-naïve patients in the advanced/metastatic setting.

5. Prior therapy with abemaciclib in the metastatic setting. Note: Use of abemaciclib in the adjuvant setting is allowed if the last treatment administration was more than 12 months prior to first recurrence.

6. Prior therapy with elacestrant or other investigational SERDs, or investigational alike agents such as SERMs, SERCANs, CERANs, and PROTACs in the metastatic setting.

7. Patient has a concurrent malignancy or malignancy within 3 years of enrollment, with the exception of adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or second primary breast cancer.

8. Currently participating in another breast cancer intervention clinical study. Patients who are being followed for overall survival for another clinical trial with no therapy and study intervention are allowed after the washout period for any prior therapy.

9. Prior anti-cancer or investigational drug treatment within the following windows:

   • Fulvestrant treatment (last injection) <42 days before first dose of study drug
   • Any other endocrine therapy <14 days before first dose of study drug. Note: LHRH agonists should not be counted as endocrine therapy.
   • Chemotherapy or other anti-cancer therapy <14 days before first dose of study drug
   • Any investigational anti-cancer drug therapy within <28 days or <5 half lives, whichever is shorter
   • Bisphosphonates or RANKL inhibitors initiated, or dose changed <1 month prior to first dose of study drug.

10. Radiation therapy (other than CNS directed) within 14 days before the first dose of study drug. CNS directed radiation therapy within 28 days before the first dose of study drug.

11. Uncontrolled significant active infections

    • Patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection must have undetectable viral load during screening
    • Patients known to be HIV+ are allowed as long as they have undetectable viral load at baseline.

12. Major surgery within 4 weeks of starting trial therapy.

13. Inability to take oral medication, or history of malabsorption syndrome or any other uncontrolled gastrointestinal condition.

14. Females of childbearing potential who do not agree to use a highly effective non-hormonal method of contracept

    ion and to abstain from donating ova within 28 days of the first dose of study treatment through 120 days after the last dose of study treatment. Highly effective non-hormonal method of contraception includes any of the following:

    1. Intrauterine device (non-hormonal)
    2. Sexual abstinence
    3. Bilateral tubal occlusion/ligation
    4. Have a vasectomized partner with confirmed azoospermia.

15. Male patients (including males with a vasectomy) with a pregnant or non-pregnant female of childbearing potential partner who do not agree to use a highly effective barrier contraception method (condoms) within 28 days ofthe first dose of study treatment until 120 days of the last dose of study treatment. And male patients who do not agree to abstain from donating sperm within the same period. In addition, female partners of childbearing potential, of male patients (who has not undergone vasectomy) must use highly effective methods of contraception.

16. Females who are pregnant or breastfeeding. Females should not get pregnant during study treatment and for 120 days after last dose of study treatment. Females should not breastfeed during administration of elacestrant and for 1 week after receiving the last dose.

17. Known intolerance to either study drug or any of the excipients.

18. Patients currently receiving or received any of the following medications prior to first dose of trial therapy:

    1. Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 (including foods and herbal preparations) within 14 days or <5 half-lives, whichever is shorter)
    2. Herbal preparations/medications (which are not strong or moderate inducers or inhibitors of CYP3A4). These include, but are not limited to , kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng within 7 days prior to initiating trial therapy
    3. Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization.

19. Any severe medical or psychiatric condition that in the opinion of the investigator(s) would preclude the patient's participation in a clinical study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2	Elacestrant	Elacestrant in combination with abemaciclib at the recommended phase 2 dose (RP2D) determined in phase 1b
Phase 1b Cohort 2	Elacestrant	Elacestrant 400 mg QD + abemaciclib 100 mg BID
Phase 1b Cohort 1	Abemaciclib	Elacestrant 300 mg once daily (QD) + abemaciclib 100 mg twice daily (BID)
Phase 1b Cohort 1	Elacestrant	Elacestrant 300 mg once daily (QD) + abemaciclib 100 mg twice daily (BID)
Phase 1b Cohort 2	Abemaciclib	Elacestrant 400 mg QD + abemaciclib 100 mg BID
Phase 1b Cohort 3	Elacestrant	Elacestrant 400 mg QD + abemaciclib 150 mg BID
Phase 2	Abemaciclib	Elacestrant in combination with abemaciclib at the recommended phase 2 dose (RP2D) determined in phase 1b
Phase 1b Cohort 3	Abemaciclib	Elacestrant 400 mg QD + abemaciclib 150 mg BID

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	3 years	Defined as the proportion of patients with a best overall response (BOR) of either a complete response or partial response per blinded independent central review, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
Recommended phase 2 dose (RP2D)	1 year	Based on the observed number of dose-limiting toxicities (DLTs) during the first cycle. Dose-limiting toxicity is based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. DLTs will be evaluated during the first cycle (28 days) of treatment in up to 3 cohorts during Phase 1b. A DLT will be defined as any of the toxicities listed in the protocol that are not clearly due to breast cancer or extraneous causes.

Secondary Outcome Measures

Name	Time	Method
Intracranial Response Rate (RR) per RECIST v1.1	3 years	Defined as the proportion of patients achieving a best overall response of confirmed partial response + complete response, based on intracranial lesions per RECIST v1.1 and blinded independent central review.
Duration of Tumor Response (DOR)	3 years	Defined as the duration of time from the date when criteria are met for either a complete response or partial response, per RECIST v1.1, until the first date that progressive disease is objectively documented, per blinded independent central review.
Intracranial RR per Response Assessment in Neuro-Oncology (RANO)	3 years	Defined as the proportion of patients achieving a best overall response of confirmed partial response plus complete response, based on intracranial lesions (per RANO criteria) and per blinded independent central review.
Progression-Free Survival (PFS)	3 years	Defined as the time elapsing between the start of treatment and the date of the earliest evidence of objective disease progression or death of any cause before documented disease-progression assessed through study completion.
Clinical Benefit Rate (CBR)	3 years	Defined as the proportion of patients who have the best overall response a complete response, a partial response, or stable disease.

Trial Locations

Locations (79)

Providence Medical Foundation; 🇺🇸 Fullerton, California, United States

California Research Institute; 🇺🇸 Los Angeles, California, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

Miami Valley Hospital South; 🇺🇸 Centerville, Ohio, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

SCRI Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

UT Health San Antonio University of Texas; 🇺🇸 San Antonio, Texas, United States

Virginia Cancer Institute; 🇺🇸 Norfolk, Virginia, United States

Antwerp University Hospital; 🇧🇪 Edegem, Belgium

Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg; 🇧🇪 Leuven, Belgium

Universite Catholique de Louvain (UCL) - Cliniques Universitaires Saint-Luc; 🇧🇪 Woluwe-Saint-Lambert, Belgium

Institut de Cancerologie de l'Ouest site Paul Papin; 🇫🇷 Angers, France

Hôpital Morvan - CHRU de Brest - cancérologie et d'hématologie; 🇫🇷 Brest, France

Centre Francois Baclesse - Oncologie Medicale - Cancerolo; 🇫🇷 Caen, France

Centre Jean Perrin; 🇫🇷 Clermont-Ferrand, France

Centre Léon Bérard - Département Oncologie Médicale; 🇫🇷 Lyon, France

Centre de Cancerologie du Grand Montpellier; 🇫🇷 Montpellier, France

Hôpital de la Pitiê Salpêtriêre; 🇫🇷 Paris, France

Centre Hospitalier Universitaire de Poitiers; 🇫🇷 Poitiers, France

Institut Claudius Regaud; 🇫🇷 Toulouse, France

Klinikum Bayreuth GmbH; 🇩🇪 Bayreuth, Germany

Uniklinik Koeln - Klinik und Poliklinik fuer Frauenheilkunde; 🇩🇪 Cologne, Germany

Universitatsklinikum Carl Gustav Carus; 🇩🇪 Dresden, Germany

Universitaetsklinikum Duesseldorf; 🇩🇪 Düsseldorf, Germany

Universitätsklinikum Erlangen; 🇩🇪 Erlangen, Germany

Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Germany

Klinikum Worms gGmbH; 🇩🇪 Worms, Germany

Helios Klinikum Wuppertal; 🇩🇪 Wuppertal, Germany

National and Capodistrian University of Athens - University General Hospital Attikon; 🇬🇷 Athens, Greece

Metropolitan Hospital [Oncology]; 🇬🇷 Piraeus, Greece

EUROMEDICA General Clinic of Thessaloniki; 🇬🇷 Thessaloníki, Greece

Interbalkan European Medical Center; 🇬🇷 Thessaloníki, Greece

AOU Ospedali Riuniti Umberto I-G.M.Lancisi -G.Salesi; 🇮🇹 Ancona, Italy

Istituto di Candiolo, IRCCS; 🇮🇹 Candiolo, Italy

Istituto Romagnolo per lo Studio dei Tumori Dino Amadori - IRST IRCCS; 🇮🇹 Meldola, Italy

A. O. Ospedali Riuniti Parpardo, Piemonte, Messina; 🇮🇹 Messina, Italy

IEO - Istituto Europeo di Oncologia, IRCCS; 🇮🇹 Milano, Italy

Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena; 🇮🇹 Modena, Italy

Ospedale San Gerardo, ASST di Monza, IRCCS; 🇮🇹 Monza, Italy

Azienda Ospedaliera Universitaria Federico II; 🇮🇹 Napoli, Italy

Istituto Nazionale dei Tumori - Fondazione Pascale, IRCCS; 🇮🇹 Napoli, Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS; 🇮🇹 Roma, Italy

Azienda Ospedaliera Santa Maria di Terni; 🇮🇹 Terni, Italy

AOU Città della Salute e della Scienza di Torino, Ospedale Molinette; 🇮🇹 Torino, Italy

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Gangnam Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Ewha Womans University MokDong Hospital; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Bundang Hospital; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

University Hospital Reina Sofía; 🇪🇸 Córdoba, Andalusia, Spain

University Hospital Ramón y Cajal; 🇪🇸 Madrid, Community Of Madrid, Spain

University Hospital 12 de Octubre; 🇪🇸 Madrid, Community Of Madrid, Spain

Clara Campal Comprehensive Cancer Center (CIOCC); 🇪🇸 Madrid, Community Of Madrid, Spain

University Clinical Hospital Virgen de la Arrixaca; 🇪🇸 El Palmar, Murcia, Spain

Hospital Clinic De Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall D Hebron; 🇪🇸 Barcelona, Spain

Clinica Universidad de Navarra; 🇪🇸 Pamplona, Spain

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Hospital Universitario Quirónsalud Madrid; 🇪🇸 Madrid, Spain

Complexo Hospitalario Universitario De Santiago; 🇪🇸 Santiago De Compostela, Spain

Fundación Instituto Valenciano De Oncología; 🇪🇸 Valencia, Spain

Hospital Universitario Virgen del Rocío; 🇪🇸 Valencia, Spain

Adana Sehir Hastanesi; 🇹🇷 Adana, Turkey

Ankara Bilkent Sehir Hastanesi Tibbi Onkoloji Klinigi; 🇹🇷 Ankara, Turkey

Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi; 🇹🇷 Ankara, Turkey

Gulhane Egitim ve Arastirma Hastanesi Tibbi Onkoloji Klinigi; 🇹🇷 Ankara, Turkey

Hacettepe University Medical Faculty; 🇹🇷 Ankara, Turkey

Memorial Ankara Hastanesi Tibbi Onkoloji; 🇹🇷 Ankara, Turkey

Ege University Medical Faculty; 🇹🇷 Bornova, Turkey

Prof. Dr. Suleyman Yalcin Sehir Hastanesi; 🇹🇷 Istanbul, Turkey

University Hosiptals of Leicester NHS Trust -Glenfield Hospital; 🇬🇧 Leicester, United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust; 🇬🇧 Liverpool, United Kingdom

Guy's and St Thomas' NHS Foundation Trust; 🇬🇧 London, United Kingdom

University College London Hospitals NHS Foundation Trust - University College Hospital (UCH) - Macmillan Cancer Centre; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust - Medical Oncology; 🇬🇧 Manchester, United Kingdom