Title
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)

Description
This is a multicenter, Phase 1b/2 trial. The Phase 1b aims at selecting the RP2D dose, defined as a dose that is associated with less than 33% of patients experiencing a DLT of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, and ribociclib, that is, ≤1 patient experiencing a DLT out of 6 DLT evaluable patients. For each combination, this phase will have between 1 and 3 cohorts of 6 DLT-evaluable patients each. The total number of DLT-evaluable patients in all the combinations will vary between 24 and 72.

The Phase 2 part of the trial will evaluate the efficacy and safety of the various combinations in patients with ER+/HER2- advanced/metastatic breast cancer.

Objective
Phase 1b Primary:
1. Determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with each of the other study drugs.

Phase 1b Secondary:
1. Characterize the safety of elacestrant in combination with each of the other study drugs.
2. Describe the plasma (blood for everolimus) pharmacokinetics (PK) of elacestrant and each of the combination drugs and their major metabolites and explore any potential drug-drug interactions.
3. Evaluate the efficacy of elacestrant in combination with each of the other study drugs for overall response rate (ORR) as per RECIST v. 1.1, duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS).

Phase 2 Primary:
1. Evaluate the efficacy of elacestrant in combination with each of the other drugs for PFS.

Phase 2 Secondary:
1. Evaluate the efficacy of elacestrant in combination with each of the other drugs for additional efficacy endpoints.
2. Further characterize the safety of elacestrant in combination with each of the other study drugs.

Treatment The treatment arms will be:

Arm A: 50 patients: elacestrant with alpelisib;

Arm B: 50 patients: elacestrant with everolimus;

Arm C: 60 patients (30 patients in each combination): elacestrant with either abemaciclib or ribociclib;

Arm D: 90 patients (30 patients in each combination): elacestrant with either palbociclib, abemaciclib, or ribociclib

Key Eligibility Inclusion Criteria:

Patient has signed the informed consent before all study specific activities are conducted.

Women or men aged >/=18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature. Female patients may be either postmenopausal, 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 surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose of trial therapy).



Premenopausal and perimenopausal women and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated at least 4 weeks before the start of trial therapy and are planning to continue LHRH agonist treatment during the study.

For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml.



Histopathologically or cytologically confirmed ER+, HER2-, breast cancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018).Note: In the context of this trial, ER status will be considered positive if >/=10% of tumor cells demonstrate positive nuclear staining by immunohistochemistry.

At least one measurable lesion as per RECIST version 1.1 or a mainly lytic bone lesion. Note: Patients with stable brain or subdural metastases are allowed if the patient has completed local therapy and was on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. The dose must be
ECOG performance status of 0 or 1.

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
Cockcroft-Gault based creatinine clearance ≥50 mL/min.
Note:
• Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72)
• Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72)

Serum albumin >/=3.0 g/dL (>/=30 g/L)

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is

Applicable Disease Sites
Breast

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital