This study has 2 phases: a Phase 1b evaluation of elacestrant in combination with abemaciclib followed by a Phase 2 evaluation of elacestrant in combination with abemaciclib in women and men with brain metastases from ER positive, HER-2 negative breast cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stemline Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 May 2023 → ongoing

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Stemline Therapeutics, Inc.

External identifiers

EU CT number

2024-512878-98-00

EudraCT number

2022-001087-10

ClinicalTrials.gov

NCT05386108

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Pharmacokinetic, Pharmacodynamic, Safety

Phase 1b: Phase 1b: Determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with abemaciclib in participants with metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor2 (HER-2) negative breast cancer.
Phase 2: Evaluate the efficacy of elacestrant in combination with abemaciclib, in terms of ORR (per RECIST version 1.1) in ER positive, HER-2 negative breast cancer in participants with brain metastases.

Secondary objectives 5

1. Phase 1b - Characterize the safety of elacestrant in combination with abemaciclib.
2. Phase 1b - Describe the plasma pharmacokinetics (PK) of elacestrant and abemaciclib when administered in combination.
3. Phase 1b - 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).
4. Phase 2 • Evaluate the efficacy of elacestrant in combination with abemaciclib in terms of: o Intracranial objective response rate (iORR), per intracranial RECIST version 1.1. iORR, per the Response Assessment in Neuro-Oncology for Brain Metastases (RANO- BN) Working Group criteria (Lin et al., 2015) DoR, CBR, PFS and OS.
5. Phase 2 • Describe the plasma PK profile of elacestrant and abemaciclib when administered in combination.

Conditions and MedDRA coding

Brain Metastasis from Estrogen Receptor Positive, HER-2 Negative Breast Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Patient has signed the informed consent form before any study-related activities according to local guidelines.
2. 11. Patient has adequate bone marrow and organ function, as defined by the following laboratory values: a. Absolute neutrophil count (ANC) ≥1.5 × 109/L. b. Platelets ≥100 × 109/L. c. Hemoglobin ≥9.0 g/dL. d. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE Grade ≤1. e. Creatinine clearance (per Cockcroft-Gault formula [Appendix E]) ≥50 mL/min f. Serum albumin ≥3.0 g/dL (≥30 g/L). g. 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. h. 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.
3. 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: a) Age ≥60 years. b) Age <60 years and amenorrhea for 12 or more months (without an alternative cause) and follicle stimulating hormone (FSH) and estradiol in postmenopausal ranges per local reference ranges. c) Documentation of prior bilateral oophorectomy, at least 1 month before the first dose of trial therapy). − Pre-menopausal /peri-menopausal women and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 3-4 weeks before the start of trial therapy and is planning to continue LHRH during the study.
4. 3. Patient must have ER positive, HER-2 negative tumor status as confirmed by local laboratory testing in the following manner: o Documentation of ER positive tumor with ≥ 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 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).
5. 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 demonstrating unequivocal progression in the opinion of the treating investigator 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 ≥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.
6. 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.
7. 7. Patients’ prior therapy received in the metastatic setting includes: − At least one endocrine therapy. − Up to two chemotherapy regimens. − Up to two lines of prior cyclin-dependent kinase (CDK) 4/6 inhibitor, not including abemaciclib. Note 1: Toxicity from prior therapy must be resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2). Note 2: Chemotherapy refers to not targeted cytotoxic agents (e.g., alkylating agents, taxanes, nucleotide analogs, platinum-based drugs, vinca alkaloids, etc) and antibody drug conjugates (ADCs). Targeted therapies (e.g., kinase inhibitors) are not considered chemotherapy for eligibility purposes. Not targeted cytotoxic agents administered for less than 1 cycle will not be counted as a prior chemotherapy regimen.
8. 8. Patient has documented intracranial and/or extracranial clear radiological progression or recurrence while on or after the most recent therapy.
9. 9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
10. 6. Patients have experienced no more than one seizure within 4 weeks prior to starting trial therapy;
11. 10. Patient has a life expectancy ≥ 12 weeks;

Exclusion criteria 19

1. 1. Immediate CNS-specific treatment is likely to be required, per the treating physician's assessment.
2. 11. Radiation therapy (including CNS directed) within 7 days before the first dose of study drug, or without a full recovery from radiotherapy acute effects;
3. 12. Uncontrolled significant active infections. • Patients with hepatitis B virus (HBV) and / or hepatitis C virus (HCV) infection must have undetectable viral load (or detected below the lower limit of quantification) during screening. • Patients known to be HIV+ are allowed as long as they have undetectable viral load (viral suppression) at baseline.
4. 13. Major surgery within 4 weeks of starting trial therapy.
5. 14. Inability to take oral medication, or history of malabsorption syndrome or any other uncontrolled gastrointestinal condition that may significantly alter the absorption of study drugs;
6. 15. Females of childbearing potential who do not agree to use a highly effective non-hormonal method of contraception 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: a. Intrauterine device (non-hormonal). b. Sexual abstinence. c. Bilateral tubal occlusion/ligation. d. Have a vasectomized partner with confirmed azoospermia. Note: Please refer to Appendix F for further details.
7. 16. Male patients (including males after a vasectomy) with a pregnant or nonpregnant female of childbearing potential partner who do not agree to use a highly effective barrier contraception method (condoms) within 28 days of the 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 freezing or 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, as described in Appendix F.
8. 17. 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.
9. 18. Known intolerance to either study drug or any of the excipients.
10. 19. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy: a. 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, (Refer to Section 6.3.3). b. 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), ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng within 7 days prior to initiating trial therapy. Please see the protocol for further exclusion criteria
11. 2. Patient with imminent organ failure and/or visceral crisis.
12. 3. Patient has leptomeningeal metastases, defined as having positive CSF cytology or unequivocal radiologic and clinical evidence of leptomeningeal involvement.Note: Discrete dural metastases are permitted;
13. 4. Breast cancer treatment-naïve patients (i.e., not having received any systemic therapy) in the advanced / metastatic setting.
14. 6. 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.
15. 7. Prior therapy with elacestrant or other investigational SERDs, or investigational alike agents such as SERMs, SERCANs, CERANs, and PROTACs, in the metastatic setting.
16. 8. 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; and any other malignancy that is considered in complete remission by the Investigator(s) that is approved by the Medical Monitor;
17. 9. 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
18. 10. Prior anticancer 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 alone should not be counted as endocrine therapy. • Chemotherapy or other anticancer therapy <14 days before first dose of study drug. • Any investigational anticancer drug therapy within <28 days or <5 halflives, whichever is shorter. • Bisphosphonates or RANKL inhibitors initiated, or dose changed <1 month prior to first dose of study drug according to institutional guidelines.
19. 5. History of pulmonary embolism (PE), cardiovascular accident (CVA), myocardial infarction (MI) in the past 6 months from screening visit;

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1b: The primary study endpoint is determination of the RP2D based on the observed number of DLTs during the first cycle.
2. Phase 2:− ORR per overall RECIST version 1.1;; defined as the proportion of participants achieving a best overall response of confirmed partial response (PR) or confirmed complete response (CR), per BICR.

Secondary endpoints 23

1. Phase 1b: − AEs and serious adverse events (SAEs) and changes in clinical laboratory values, vital signs measurements and ECG parameters.
2. Phase 1b: − 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.
3. Phase 1b: − ORR, DoR, CBR at 16 weeks, CBR at 24 weeks, and PFS as per local investigator's assessment and per blinded independent central review (BICR)..
4. Phase 1b: − OS.
5. Phase 2: − DoR per overall RECIST version 1.1 per BICR.
6. Phase 2: − Plasma PK parameters including, but not limited to AUC0-tau, Cmax, Tmax, and Ctrough.
7. Phase 2: − Change in participants’ responses to EORTC QLQ-C30, EQ5D-5L, and EORTC QLQ-BN20.
8. Phase 2: − Change in participants’ scores in MMSE-2 SV, and NANO scale.
9. Phase 2: − AEs and SAEs and changes in clinical laboratory values, vital signs measurements and ECG parameters
10. Phase 2: - iORR per RANO-BM (iORR-RANO) per BICR
11. Phase 2: - iORR per intracranial RECIST version 1.1 (iORR-RECIST) per BICR
12. Phase 2: Intracranial DoR per RANO--BM (iDoR-RANO) per BICR
13. Phase 2: Intracranial DoR per intracranial RECIST version 1.1 (iDoR-RECIST) per BICR
14. Phase 2: CBR per overall RECIST version 1.1at 16 weeks (CBR-16w) per BICR
15. Phase 2: Intracranial CBR per RANO-BM at 16 weeks (iCBR-RANO-16w) per BICR
16. Phase 2: Intracranial CBR per intracranial RECIST version 1.1at 16 weeks (iCBR-RECIST-16w) per BICR
17. Phase 2: CBR per overall RECIST version 1.1 at 24 weeks (CBR-24w) per BICR
18. Phase 2:Intracranial CBR per RANO-BM at 24 weeks (iCBR-RANO-24w) per BICR
19. Phase 2: Intracranial CBR per intracranial RECIST version 1.1 at 24 weeks (iCBR-RECIST-24w) per BICR
20. Phase 2:PFS per overall RECIST version 1.1 per BICR
21. Phase 2: Intracranial PFS (iPFS) per BICR
22. Phase 2: All the above endpoints will be also assessed per local reading
23. Phase 2: OS is defined as the length of time from first intake until the date of death from any cause

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stemline Therapeutics Inc.

Sponsor organisation

Stemline Therapeutics Inc.

Address

750 Lexington Avenue

City

New York

Postcode

10022-1200

Country

United States

Scientific contact point

Organisation

Stemline Therapeutics Inc.

Contact name

Clinical Development and Clinical Operations

Public contact point

Organisation

Stemline Therapeutics Inc.

Contact name

Clinical Development and Clinical Operations

Third parties 10

Locations

6 EU/EEA countries · 54 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 50 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications