Open-Label Umbrella Study To Evaluate Safety And Efficacy Of Elacestrant In Various Combination In Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a multicenter, Phase 1b/2 trial. The phase 1b part of the trial aims to determine the RP2D of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, and ribociclib. 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.

Detailed Description
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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. 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 The total number of patients in Phase 2 for all treatment arm combinations will be 250 patients

Official Title
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A Phase 1b/2, Open-Label Umbrella Study To Evaluate Safety And Efficacy Of Elacestrant In Various Combination In Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Elacestrant
* Drug: Alpelisib
* Drug: Everolimus
* Drug: Ribociclib
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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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 ≤2.0 mg/day of dexamethasone or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 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 ≤1 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) ≤ 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. Exclusion Criteria: Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver involvement >50%. Prior chemotherapy or elacestrant in the advanced/metastatic setting. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. 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. Documented pneumonitis/ILD prior to Cycle 1 Day 1. Major surgery within 28 days before starting trial therapy. Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impact the absorption of the study drug. Known intolerance to elacestrant or any of its excipients (see Table 18). Females of childbearing potential who: Within 28 days before starting trial therapy, did not use a highly effective method of contraception. Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after trial therapy discontinuation Men who do not agree to abstain from donating sperm, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days thereafter. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy: • Investigational anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter, Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives, whichever is shorter, (Refer to http://medicine.iupui.edu/clinpharm/ddis/), Herbal preparations/medications within 7 days. These include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng, Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization. Evidence of ongoing alcohol or drug abuse as assessed by the investigator. Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A) Inclusion: PIK3CA mutation by local laboratory assessment. One or two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: Prior therapy with alpelisib or any other PI3K inhibitor. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140 mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%). Known intolerance to alpelisib or any of its excipients. Patient is currently receiving or received drugs known to be a BCRP inhibitor within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates or denosumab Additional Eligibility for the Everolimus Combination (Phase 1b and Arm B) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: Prior therapy with everolimus. Known intolerance to everolimus or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm C) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: Prior therapy with abemaciclib in the metastatic setting. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: Prior therapy with ribociclib in the metastatic setting. Known intolerance to ribociclib or any of its excipients. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy. Additional Eligibility for the Palbociclib Combination (Phase 1b) Inclusion: 1. None. Exclusion: Prior therapy with palbociclib in the metastatic setting. Known intolerance to palbociclib or any of its excipients Additional Eligibility for the Palbociclib Combination (Arm D) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting. Exclusion: Prior therapy with a CDK4/6i in the metastatic setting. Known intolerance to palbociclib or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm D) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting. Exclusion: Prior therapy with a CDK4/6i in the metastatic setting. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for Ribociclib Combination (Arm D) Inclusion: 1. One or two prior hormonal therapies in the metastatic setting. Exclusion: Prior therapy with a CDK4/6i in the metastatic setting. Known intolerance to ribociclib or any of its excipients. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Arm A: elacestrant with alpelisib<br>Elacestrant 258mg or 345mg + Alpelisib 250 mg or 300 mg | Drug: Elacestrant<br>* Elacestrant 86mg, 172mg, 258mg or 345mg QD in cycles of 28 days<br>Drug: Alpelisib<br>* Alpelisib 250 mg or 300 mg QD in cycles of 28 days<br>* Other names: PIQRAY;|
| Experimental: Phase 1b Arm B: elacestrant with everolimus<br>Elacestrant 258mg or 345mg + Everolimus 5.0mg, 7.5mg or possibly 10 mg | Drug: Elacestrant<br>* Elacestrant 86mg, 172mg, 258mg or 345mg QD in cycles of 28 days<br>Drug: Everolimus<br>* Everolimus 5.0mg, 7.5mg, or 10mg QD in cycles of 28 days<br>* Other names: Afinitor;|
| Experimental: Phase 1b Arm C: elacestrant with abemaciclib or ribociclib:<br>Elacestrant 86 mg, 172 mg, 258 mg + Ribociclib 400 mg or possibly 600mg The recommended Phase 2 dose for the combination of elacestrant and abemaciclib is evaluated in the ongoing ELECTRA trial (ClinicalTrials.gov Identifier: NCT04791384) | Drug: Elacestrant<br>* Elacestrant 86mg, 172mg, 258mg or 345mg QD in cycles of 28 days<br>Drug: Ribociclib<br>* ribociclib 400mg or 600mg once daily for 21 days followed by 7 days off in cycles of 28 days<br>* Other names: KISQALI;|
| Experimental: Phase 1b Arm D: elacestrant with either palbociclib, abemaciclib, or ribociclib (no prior CDK4/6i)<br>Elacestrant 258mg or 345mg + Palbociclib 100 mg,125 mg OR The recommended Phase 2 dose for the combination of elacestrant and abemaciclib is evaluated in the ongoing ELECTRA trial (ClinicalTrials.gov Identifier: NCT04791384) Elacestrant 86 mg, 172 mg, 258 + Ribociclib 400 mg or possibly 600mg | Drug: Elacestrant<br>* Elacestrant 86mg, 172mg, 258mg or 345mg QD in cycles of 28 days<br>Drug: Ribociclib<br>* ribociclib 400mg or 600mg once daily for 21 days followed by 7 days off in cycles of 28 days<br>* Other names: KISQALI;Drug: Palbociclib<br>* palbociclib 100 mg or 125mg once a day for 21 days followed by 7 days off in cycles of 28 days<br>* Other names: IBRANCE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with each of the other study drugs | The recommended Phase 2 dose (RP2D) will be determined as the dose that is associated with less than 33% of patients (</+ 1 patient out of 6) experiencing a dose-limiting toxicities (DLTs) during the first cycle. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the safety of elacestrant in combination with each of the other study drugs | Number of Participants with Adverse events (AEs), serious adverse events (SAEs), with abnormal laboratory tests values, abnormal vital sign and abnormal electrocardiograms (ECG) | 24 months | 
| Pharmacokinetic assessment profile of elacestrant and each of the combination drugs. | Describe the plasma pharmacokinetics (PK) of elacestrant and each of the combination drugs. | 36 months | 
| Overall Response Rate | proportion of patients who achieve a best overall response (BOR) of confirmed partial response (PR) or complete response (CR) | 36 months | 
| Duration of Response | time from the date of the first documented CR/PR until the first radiological documentation of disease progression or death | 36 months | 
| Clinical Benefit Rate | Defined as the proportion of patients who have the best overall response with a complete response, partial response or stable disease. | 36 months | 
| Progression-free survival | Time from the date of the first dose to the date of the first radiological documentation of disease progression or death, whichever occurs first | 36 months | 
| Overall Survival | Time from the date of the first dose to the date of death from any cause | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer