Study of Abemaciclib and Elacestrant in Patients With Brain Metastasis Due to HR+/HER2- Breast Cancer

Study Overview
=================
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 with or without brain metastases from ER-positive, HER-2 negative breast cancer. Phase 1b is designed to select the recommended phase 2 dose and will be followed by a phase 2 evaluation of elacestrant in combination with abemaciclib in patients with active brain metastases from ER-positive, HER-2 negative 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

Conditions
-----------------
Breast Neoplasms, Brain Neoplasms, Neoplasms by Site, Neoplasms, Breast Diseases, Central Nervous System Neoplasms, Brain Diseases, Central Nervous System Diseases

Intervention / Treatment
-----------------
* Drug: Elacestrant
* Drug: Abemaciclib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient has the signed informed consent form before any study-related activities according to local guidelines. 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: Age ≥60 years 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 Documentation of prior bilateral oophorectomy, at least 1 month before first dose of trial therapy). 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 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. Any neurological symptoms of brain metastases must be stable for at least 2 weeks before starting trial therapy. 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). Patient has documented intra- and/or extra-cranial radiological progression or recurrence while on or after the most recent therapy. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 Patient has adequate bone marrow and organ function, as defined by the following laboratory values: Absolute neutrophil count (ANC) ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9.0 g/dL 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) Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/min Serum albumin ≥3.0 g/dL (≥30 g/L) 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 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 The patient is able and willing to adhere to the study visit schedule and other protocol requirements. 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: Newly diagnosed brain metastasis in patients who never received prior CNS-directed therapy. Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy 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: Immediate CNS-specific treatment is likely to be required, per the treating physician's assessment. Patient has imminent organ failure and/or visceral crisis. Patient has leptomeningeal metastases, defined as having positive CSF cytology or unequivocal radiologic or clinical evidence of leptomeningeal involvement. 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. 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. Prior therapy with elacestrant or other investigational SERDs, or alike agents such as SERMs, SERCANs, CERANs, and PROTACs in the metastatic setting. 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. 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. 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. Radiation therapy (other than CNS directed) within 14 days before the first dose of study drug. 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. Major surgery within 4 weeks of starting trial therapy. Inability to take oral medication, or history of malabsorption syndrome or any other uncontrolled gastrointestinal condition. 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: Intrauterine device (non-hormonal) Total abstinence Bilateral tubal occlusion/ligation Have a vasectomized partner with confirmed azoospermia. 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. Females who are breastfeeding or pregnant. Known intolerance to either study drug or any of the excipients. Patients currently receiving or received any of the following medications prior to first dose of trial therapy: Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 21 days prior to initiating trial therapy 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 Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization. Any severe medical or psychiatric condition that in the opinion of the investigator(s) would preclude the patient's participation in a clinical study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Cohort 1<br>Elacestrant 300 mg once daily (QD) + abemaciclib 100 mg twice daily (BID) | Drug: Elacestrant<br>* 300 mg, 400 mg<br>* Other names: ELA-0121;Drug: Abemaciclib<br>* 100 mg, 150 mg<br>* Other names: Verzenio;|
| Experimental: Phase 1b Cohort 2<br>Elacestrant 400 mg QD + abemaciclib 100 mg BID | Drug: Elacestrant<br>* 300 mg, 400 mg<br>* Other names: ELA-0121;Drug: Abemaciclib<br>* 100 mg, 150 mg<br>* Other names: Verzenio;|
| Experimental: Phase 1b Cohort 3<br>Elacestrant 400 mg QD + abemaciclib 150 mg BID | Drug: Elacestrant<br>* 300 mg, 400 mg<br>* Other names: ELA-0121;Drug: Abemaciclib<br>* 100 mg, 150 mg<br>* Other names: Verzenio;|
| Experimental: Phase 2<br>Elacestrant in combination with abemaciclib at the recommended phase 2 dose (RP2D) determined in phase 1b | Drug: Elacestrant<br>* 300 mg, 400 mg<br>* Other names: ELA-0121;Drug: Abemaciclib<br>* 100 mg, 150 mg<br>* Other names: Verzenio;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RP2D | 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. Dose-limiting toxicities 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. | 1 year | 
| Objective Response Rate | Defined as the proportion of patients with a best overall response of either a complete response or partial response per blinded independent central review, per RECIST version 1.1. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Response Rate per Response Evaluation Criteria in Solid Tumors (RECIST) | Defined as the proportion of patients achieving a best overall response of confirmed partial response + complete response, based on intracranial lesions per RECIST version 1.1 and blinded independent central review. | 3 years | 
| Intracranial Response Rate per Response Assessment in Neuro-Oncology (RANO) | 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. | 3 years | 
| Duration of Tumor Response | 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. | 3 years | 
| Clinical Benefit Rate | Defined as the proportion of patients who have the best overall response a complete response, a partial response, or stable disease. | 3 years | 
| Duration of Progression-Free Survival | 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. | 3 years |