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 premenopausal or perimenopausal.
Postmenopausal status is defined by:
1. Age ≥60 years. 2. Age <60 years and amenorrhea for 12 or more months (in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a follicle
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (140
pmol/L) or 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 either from a fresh biopsy or from an archival tissue obtained no
more than 2 years prior to signing of the informed consent form.
- - ER and HER-2 testing must be performed 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. 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.
5. Any neurological symptoms of brain metastases must be stable for at least 2 weeks
before starting trial therapy.
6. Patient has received prior therapy in the metastatic setting including:
- - At least one endocrine therapy.
- - Up to two chemotherapy regimens.
- - Up to two prior CDK 4/6 inhibitors, not including abemaciclib.
- - If recurrence was observed while on adjuvant therapy or within 12 months of end
of adjuvant therapy, this therapy will be counted as part of required prior
therapy for eligibility.
- - 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).
7. Patient has documented intra- and/or extra-cranial radiological progression or
recurrence while on or after the most recent therapy.
8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 9. 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. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤3.0 × 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. 10. The patient is able and willing to adhere to the study visit schedule and other
protocol requirements.
11. For Phase 1b, the presence of brain metastases is allowed but not required for
eligibility. 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
CNS-directed therapy.
2. Newly diagnosed brain metastasis outside any area that was previously
subjected to CNS-directed therapy. 3. Brain metastases that are 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 magnetic resonance imaging (MRI).
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 or clinical evidence of leptomeningeal involvement.
4. Breast cancer treatment-naïve patients in the metastatic setting. Patients who
experience a recurrence while on adjuvant therapy or within 12 months of end of
adjuvant therapy are allowed.
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 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 or <5 half-lives, whichever is shorter,
before first dose of study drug.
- - Chemotherapy or other anti-cancer therapy <21 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.
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 contraception throughout within 28 days of the first dose of
study treatment until 28 days of the last dose of study treatment. Highly effective
non-hormonal method of contraception includes any of the following:
1. Intrauterine device (non-hormonal)
2. Total abstinence. 3. Bilateral tubal occlusion/ligation. 4. Have a vasectomized partner with confirmed azoospermia.
15. Men who do not agree abstain from donating sperm or to use a highly effective barrier
contraception (use condoms) during the treatment period and for 120 days thereafter.
For subjects (who have not undergone vasectomy) with female partners of childbearing
potential, the subject and his partner must, in addition to condoms, use highly
effective methods of contraception.
16. Females who are breastfeeding or pregnant.
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
within 21 days prior to initiating trial therapy. 2. Herbal preparations/medications These include, but are not limited to, St. John's
wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
yohimbe, saw palmetto, and ginseng within 21 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.