Clinical trial NCT05386108: Study of Abemaciclib and Elacestrant in Patients With Brain Metastasis Due to ER+/HER-2- Breast Cancer
Official title: An Open-label Multicenter Phase 1b-2 Study of Elacestrant in Combination With Abemaciclib in Women and Men With Brain Metastasis From Estrogen Receptor Positive, HER-2 Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Breast Neoplasms
Brain Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Central Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Lead sponsor: Stemline Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-05-23
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Recommended phase 2 dose (RP2D)
timeFrame: 1 year
measure: Objective Response Rate (ORR)
timeFrame: 3 years
Secondary outcomes:
measure: Intracranial Response Rate (RR) per RECIST v1.1
timeFrame: 3 years
measure: Intracranial RR per Response Assessment in Neuro-Oncology (RANO)
timeFrame: 3 years
measure: Duration of Tumor Response (DOR)
timeFrame: 3 years
measure: Clinical Benefit Rate (CBR)
timeFrame: 3 years
measure: Progression-Free Survival (PFS)
timeFrame: 3 years
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: Providence Medical Foundation
state: California
city: Los Angeles
country: United States
facility: California Research Institute
state: California
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Centerville
country: United States
facility: Miami Valley Hospital South
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: UT Health San Antonio University of Texas
state: Texas
city: Norfolk
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
city: Woluwe-Saint-Lambert
country: Belgium
facility: Universite Catholique de Louvain (UCL) - Cliniques Universitaires Saint-Luc
city: Angers
country: France
facility: Institut de Cancerologie de l'Ouest site Paul Papin
city: Brest
country: France
facility: Hôpital Morvan - CHRU de Brest - cancérologie et d'hématologie
city: Caen
country: France
facility: Centre Francois Baclesse - Oncologie Medicale - Cancerolo
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lyon
country: France
facility: Centre Léon Bérard - Département Oncologie Médicale
city: Montpellier
country: France
facility: Centre de Cancerologie du Grand Montpellier
city: Paris
country: France
facility: Hôpital de la Pitiê Salpêtriêre
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH
city: Cologne
country: Germany
facility: Uniklinik Koeln - Klinik und Poliklinik fuer Frauenheilkunde
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Düsseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Worms
country: Germany
facility: Klinikum Worms gGmbH
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
city: Athens
country: Greece
facility: National and Capodistrian University of Athens - University General Hospital Attikon
city: Piraeus
country: Greece
facility: Metropolitan Hospital [Oncology]
city: Thessaloníki
country: Greece
facility: EUROMEDICA General Clinic of Thessaloniki
city: Thessaloníki
country: Greece
facility: Interbalkan European Medical Center
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti Umberto I-G.M.Lancisi -G.Salesi
city: Candiolo
country: Italy
facility: Istituto di Candiolo, IRCCS
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori - IRST IRCCS
city: Messina
country: Italy
facility: A. O. Ospedali Riuniti Parpardo, Piemonte, Messina
city: Milano
country: Italy
facility: IEO - Istituto Europeo di Oncologia, IRCCS
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena
city: Monza
country: Italy
facility: Ospedale San Gerardo, ASST di Monza, IRCCS
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
city: Napoli
country: Italy
facility: Istituto Nazionale dei Tumori - Fondazione Pascale, IRCCS
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo, Università degli studi di Pavia, Pavia Fondazione IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino, Ospedale Molinette
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University MokDong Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Córdoba
country: Spain
facility: University Hospital Reina Sofía
state: Andalusia
city: Madrid
country: Spain
facility: University Hospital Ramón y Cajal
state: Community Of Madrid
city: Madrid
country: Spain
facility: University Hospital 12 de Octubre
state: Community Of Madrid
city: Madrid
country: Spain
facility: Clara Campal Comprehensive Cancer Center (CIOCC)
state: Community Of Madrid
city: El Palmar
country: Spain
facility: University Clinical Hospital Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Clinic De Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D Hebron
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Quirónsalud Madrid
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Santiago De Compostela
country: Spain
facility: Complexo Hospitalario Universitario De Santiago
city: Valencia
country: Spain
facility: Fundación Instituto Valenciano De Oncología
city: Valencia
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Adana
country: Turkey
facility: Adana Sehir Hastanesi
city: Ankara
country: Turkey
facility: Ankara Bilkent Sehir Hastanesi Tibbi Onkoloji Klinigi
city: Ankara
country: Turkey
facility: Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi
city: Ankara
country: Turkey
facility: Gulhane Egitim ve Arastirma Hastanesi Tibbi Onkoloji Klinigi
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Memorial Ankara Hastanesi Tibbi Onkoloji
city: Bornova
country: Turkey
facility: Ege University Medical Faculty
city: Istanbul
country: Turkey
facility: Prof. Dr. Suleyman Yalcin Sehir Hastanesi
city: Leicester
country: United Kingdom
facility: University Hosiptals of Leicester NHS Trust -Glenfield Hospital
city: Liverpool
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust - University College Hospital (UCH) - Macmillan Cancer Centre
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust - Medical Oncology
Study officials:
References: