Brain Metastasis from Estrogen Receptor Positive, HER-2 Negative Breast Cancer MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: Elacestrant
Product Code: [Elacestrant]
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Elacestrant
CAS Number: 722533-56-4
Current Sponsor code: RAD1901
Concentration unit:
Sponsors
Stemline Therapeutics Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient has signed the informed consent form before any studyrelated activities according to local guidelines. 2. Women or men aged equal or higher than 18 years, at the time of informed consent signature. - Female patients may be either postmenopausal or premenopausal or perimenopausal. Postmenopausal status is defined by: a) Age equeal or higher than 60 years b) Age less than 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 higher than 40 mIU/mL and an estradiol value less than 40 pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges c) Documentation of prior surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose of trial therapy). - Premenopausal or perimenopausal women must be concurrently given a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 4 weeks before the start of trial therapy and is planning to continue LHRH during the study. - For perimenopausal women to be considered of non-childbearing potential, FSH levels must be higher than 40 mIU/ml. 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. For 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. - ER and HER-2 testing must be performed in the following manner: o Documentation of ER positive tumor with equal or higher than 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 American Society for Clinical Oncology (ASCO) recommendations for ER testing (Hammond et al, 2010; Allison et al, 2020), with or without progesterone receptor (PGR) positivity o 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 (Wolff et al, 2013; Wolff et al, 2018) 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: a) Newly diagnosed brain metastasis in patients who never received prior central nervous system (CNS)-directed therapy b) Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy c) 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, the longest diameter must be equal or higher than 10 mm by CT or MRI). 5. Patients must be off corticosteroids or receiving a stable or decreasing corticosteroid dose at the time of starting trial therapy. The dose must be equal or less than 2.0 mg/day of dexamethasone or equivalent. 6. Any neurological symptoms of brain metastases must be stable for at least 4 weeks before starting trial therapy. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of s
Exclusion criteria
Exclusion criteria: 1. Immediate CNS-specific treatment is likely to be required, per the treating physician's assessment. 2. Patient has leptomeningeal metastases, defined as having positive CSF cytology or unequivocal radiologic or clinical evidence of leptomeningeal involvement. 3. 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. 4. Prior therapy with elacestrant or 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. 5. 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. 6. 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. 7. Prior anti-cancer or investigational drug treatment within the following windows: • Fulvestrant treatment (last injection) less than 42 days before first dose of study drug • Any other endocrine therapy higher than 14 days before first dose of study drug • Chemotherapy or other anti-cancer therapy less than 21 days before first dose of study drug • Any investigational anti-cancer drug therapy within higher than 28 days or less than 5 half-lives, whichever is shorter. • Bisphosphonates or RANKL inhibitors initiated or dose changed less than 3 months prior to first dose of study drug. 8. Radiation therapy (other than CNS directed) within 14 days before the first dose of study drug. 9. 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. 10. Major surgery within 4 weeks of starting trial therapy. 11. Inability to take oral medication, or history of malabsorption syndrome or any other uncontrolled gastrointestinal condition. 12. Females of childbearing potential who: - Within 28 days of study entry, did not use a highly effective method of contraception, which includes any of the following: a. Intrauterine device b. Double-barrier contraception c. Total abstinence d. Have a vasectomized partner with confirmed azoospermia. - Do not agree to use a highly effective method of contraception, as described above, throughout the entire study period and for 28 days after trial therapy discontinuation. 13. Men who do not agree abstain from donating sperm or to use a highly effective method of contraception during the treatment period and for 120 days thereafter. Highly effective methods include any of the following: a. Double-barrier contraception b. Total abstinence c. Vasectomized with confirmed azoospermia d. Female partner with intrauterine device.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1b Determine the recommended Phase 2 dose (RP2D) of this combination in patients with metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER-2) negative breast cancer. Randomized Phase 2 Evaluate the efficacy of elacestrant, alone and in combination with abemaciclib, in terms of ORR (per RECIST version 1.1) in ER positive, HER-2 negative breast cancer in patients with brain metastases.;Secondary Objective: Phase 1b • Characterize the safety of elacestrant in combination with abemaciclib. • Describe the plasma pharmacokinetics (PK) of elacestrant as well as abemaciclib and its metabolites. • Evaluate the efficacy of elacestrant in combination with abemaciclib, in terms of objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Randomized Phase 2 • Evaluate the efficacy of elacestrant, alone and in combination with abemaciclib, in terms of: o Intracranial response rate (RR), per RECIST version 1.1. o Intracranial RR, per the Response Assessment in Neuro-Oncology (RANO) Working Group criteria (Wen et al., 2017) as adapted to the assessment of brain metastases (RANO-BM). o DoR, CBR, PFS, OS.;Primary end point(s): Phase 1b: The primary study endpoint is determination of the RP2D based on the observed number of DLTs during the first cycle. Randomized Phase 2: - ORR per blinded independent central review.;Timepoint(s) of evaluation of this end point: Phase 1b: Cycle 1 (28 days) Randomized Phase 2: throughout the study duration (based on CT/MRI scans performed every 8 weeks until radiological disease progression) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: - AEs and serious adverse events (SAEs) as well as changes in clinical laboratory values, vital signs measurements and ECG parameters. - Plasma PK parameters including, but not limited to, the area under the plasma concentration-time curve over the dosing interval (AUC0-tau), Cmax, time of the maximum observed plasma concentration (Tmax), and Ctrough. - ORR, DoR, CBR, PFS, and OS. Randomized Phase 2: - Intracranial RR per blinded independent central review; defined as the proportion of patients achieving a best overall response of confirmed PR+CR, based on intracranial lesions (per RECIST version 1.1,). - Intracranial RR per blinded independent central review; defined as the proportion of patients achieving a best overall response of confirmed PR+CR, based on intracranial lesions (per RANO criteria [Wen et al., 2017]). All radiological measurements and assessments will be provided by independent central review; the clinical components required by RANO criteria will be derived from the electronic case report form. - DoR, CBR, and PFS per blinded independent central review. - ORR, intracranial RR (per RECIST version 1.1 [Appendix C]), intracranial RR (per RANO criteria [Wen et al., 2017]), DoR, CBR, PFS, and OS, per local investigator's assessment. - Plasma PK parameters including, but not limited to AUC0-tau, Cmax, Tmax, and Ctrough. - Change in patients' responses to EORTC QLQ-C30, EORTC QLQ-BN20, and EQ-5D-5L. - Change in patients' responses to MMSE-2, HVLT-R: learning and memory, and NANO scale. - AEs and SAEs as well as changes in clinical laboratory values, vital signs measurements and ECG parameters.;Timepoint(s) of evaluation of this end point: Phase 1b: Safety throughout the study duration Plasma PK based on samples collected on Cycle 1 Day 15 Radiological response throughout the study duration (based on CT/MRI scans performed every 8 weeks until radiological disease progression) Randomized Phase 2: Radiological response thr | — |
Countries
Belgium, France, Germany, Italy, Korea, Republic of, Spain, United Kingdom, United States
Contacts
Public ContactClinical Development
Stemline Therapeutics, Inc
Outcome results
None listed