A Phase 1b/2, Open-Label Umbrella Study to Evaluate Safety and Efficacy of Elacestrant in Various Combinations in Patients with Metastatic Breast Cancer (ELEVATE)

Cancer Categories

Breast

Karmanos Trial ID

2023-039

NCT ID

NCT05386108

Age Group

Adult

Scope

National

Phase

Phase I/II

Principal Investigator

Hadeel
Assad, M.D.
Oncology - Medical View Profile

Objective:

Phase 1b

Primary Objectives

Determine the RP2D of elacestrant in combination with each of the other study drugs

Secondary Objectives

Characterize the safety of elacestrant in combination with each of the other study drugs
Describe the plasma (blood for everolimus) pharmacokinetics (PK) of elacestrant and each of the combination drugs and their major metabolites and explore any potential DDIs
Evaluate the efficacy of elacestrant in combination with each of the other study drugs for ORR as per RECIST v. 1.1, DoR, CBR, PFS, and OS

Phase 2

Primary Objectives

Evaluate the efficacy of elacestrant in combination with each of the other drugs for PFS

Secondary Objectives

Evaluate the efficacy of elacestrant in combination with each of the other drugs for additional efficacy endpoints
Further characterize the safety of elacestrant in combination with each of the other study drugs.

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Eligibility

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.

Locations

Karmanos Cancer Institute - Detroit Headquarters

4100 John R
Detroit, MI 48201
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Phone: 800-527-6266

Karmanos Cancer Institute at Weisberg Cancer Center - Farmington Hills

31995 Northwestern Hwy
Farmington Hills, MI 48334
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Phone: 800-527-6266

Applicable Disease Site

Therapies, Drugs, Devices