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

• ClinicalTrials.gov Identifier: NCT05563220
• Recruitment Status: Recruiting
• First Posted: October 3, 2022
• Last Update Posted: April 8, 2024
• Sponsor: Stemline Therapeutics, Inc.
• Information provided by (Responsible Party): Stemline Therapeutics, Inc.

Tracking Information

• First Submitted Date: September 22, 2022
• First Posted Date: October 3, 2022
• Last Update Posted Date: April 8, 2024
• Actual Study Start Date: January 24, 2023
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2024)

• Number of DLTs observed during the first cycle [ Time Frame: 28 days ]
  Number of dose-limiting toxicities during the first cycle
• Estimation of PFS rate at 6 months [ Time Frame: 6 months ]
  PFS rate for each of the combination arms in patients who received prior ET and CDK4/6i in the metastatic setting

Original Primary Outcome Measures (submitted: September 28, 2022)

Determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with each of the other study drugs [ Time Frame: 18 months ]

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.

Current Secondary Outcome Measures (submitted: January 30, 2024)

• Standard PK parameters including AUC0-tau, Cmax, Tmax, and Ctrough [ Time Frame: 36 months ]
  The plasma PK of elacestrant and each of the combination drugs
• Overall Response Rate [ Time Frame: 36 months ]
  Proportion of patients who achieve a best overall response (BOR) of confirmed partial response (PR) or complete response (CR)
• Duration of Response [ Time Frame: 36 months ]
  Time from the date of the first documented CR/PR until the first radiological documentation of disease progression or death
• Clinical Benefit Rate [ Time Frame: 36 months ]
  Proportion of patients who have the best overall response with a complete response, partial response or stable disease
• Progression-free survival [ Time Frame: 36 months ]
  Time from the date of the first dose to the date of the first radiological documentation of disease progression or death, whichever occurs first
• Overall Survival [ Time Frame: 36 months ]
  Time from the date of the first dose to the date of death from any cause

Original Secondary Outcome Measures (submitted: September 28, 2022)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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, abemaciclib, 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
• Arm E: 60 patients: elacestrant with capivasertib

Phase 1b will have a total of 90 patients, while Phase 2 will have 310 patients for all treatment arm combinations.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Breast Cancer
• Metastatic Breast Cancer

Intervention

• Drug: Elacestrant
  Elacestrant 86 mg, 172 mg, 258 mg or 345 mg once daily in cycles of 28 days
• Drug: Alpelisib
  Alpelisib 250 mg or 300 mg once daily in cycles of 28 days
  Other Name: Piqray
• Drug: Everolimus
  Everolimus 5 mg, 7.5 mg, or 10 mg once daily in cycles of 28 days
  Other Name: Afinitor
• Drug: Ribociclib
  Ribociclib 400 mg or 600 mg once daily for 21 days followed by 7 days off in cycles of 28 days
  Other Name: Kisqali
• Drug: Palbociclib
  Palbociclib 100 mg or 125 mg once daily for 21 days followed by 7 days off in cycles of 28 days
  Other Name: Ibrance
• Drug: Capivasertib
  Capivasertib 200 mg or 320 mg or 400 mg twice daily for 4 days on, 3 days off in cycles of 28 days
  Other Name: Truqap
• Drug: Abemaciclib
  Abemaciclib 100 mg or 150 mg twice daily in cycles of 28 consecutive days
  Other Name: Verzenio

Study Arms

• Experimental: Phase 1b Arm A: elacestrant with alpelisib
  Elacestrant Dihydrochloride 300 mg or 400 mg + Alpelisib 250 mg or 300 mg
  Interventions:

  • Drug: Elacestrant
  • Drug: Alpelisib
• Experimental: Phase 1b Arm B: elacestrant with everolimus
  Elacestrant Dihydrochloride 300 mg or 400 mg + Everolimus 5.0 mg, 7.5 mg or possibly 10 mg
  Interventions:

  • Drug: Elacestrant
  • Drug: Everolimus
• Experimental: Phase 1b Arm C: elacestrant with abemaciclib or ribociclib:

  Elacestrant Dihydrochloride 100 mg, 200 mg, 300 mg + Ribociclib 400 mg or possibly 600 mg

  The recommended Phase 2 dose for the combination of elacestrant and abemaciclib is evaluated in the ongoing ELECTRA trial (ClinicalTrials.gov Identifier: NCT04791384)

  Interventions:

  • Drug: Elacestrant
  • Drug: Ribociclib
  • Drug: Abemaciclib
• Experimental: Phase 1b Arm D: elacestrant with either palbociclib, abemaciclib, or ribociclib (no prior CDK4/6i)

  Elacestrant Dihydrochloride 300 mg or 400 mg + 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 mg + Ribociclib 400 mg or possibly 600 mg

  Interventions:

  • Drug: Elacestrant
  • Drug: Ribociclib
  • Drug: Palbociclib
  • Drug: Abemaciclib
• Experimental: Phase 1b Arm E:
  Elacestrant Dihydrochloride 300 mg, 400 mg + Capivasertib 200 mg, 320 mg, 400 mg
  Interventions:

  • Drug: Elacestrant
  • Drug: Capivasertib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 30, 2024): 400
• Original Estimated Enrollment (submitted: September 28, 2022): 322
• Estimated Study Completion Date: August 31, 2026
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

2. 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 of any menopausal status.

   • Postmenopausal status is defined by:

     1. Age ≥60 years
     2. 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
     3. 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 (who do not fit postmenopausal criteria) 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 treatment.
   • For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml.
3. Histopathological or cytological 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, with or without PGR positivity. .
4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1 and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiable soft tissue components meeting the definition of measurability by RECIST version 1.1 that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
5. ECOG performance status of 0 or 1.

6. Patient has adequate bone marrow and organ function, as defined by the following laboratory values:

   1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L
   2. Platelets ≥100 × 10^9/L
   3. Hemoglobin ≥9.0 g/dL
   4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE grade ≤1

   5. Creatinine is ≤ 1.5 x ULN or if creatinine is > 1.5 x ULN, then creatinine clearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-G formula:

      • 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)
   6. Serum albumin ≥3.0 g/dL (≥30 g/L)
   7. 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
   8. 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:

1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. 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.
2. 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%.
3. Prior chemotherapy or elacestrant in the advanced/metastatic setting.
4. Patients with known germline BRCA mutation without prior treatment with a PARP inhibitor before study entry.
5. Prior therapy with elacestrant or other investigational selective estrogen receptor degraders (SERDs), or investigational alike agents such as selective estrogen receptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatment with fulvestrant is not exclusionary as it is an approved medication.
6. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. Other malignancies with low risk of recurrence may be considered eligible with Sponsor approval.

7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infection must have undetectable viral load during screening.

   • Patients known to be HIV+ are allowed if they have undetectable viral load at baseline.

8. Documented pneumonitis/ILD prior to Cycle 1 Day 1.
9. Major surgery within 28 days before starting trial therapy.
10. 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.
11. Known intolerance to elacestrant or any of its excipients.

12. Pregnant and breast-feeding women are excluded from the study. In addition, women of childbearing potential are excluded 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 (Appendix F) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after trial therapy discontinuation.

13. Men or women who do not agree to abstain from donating sperm or ova, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days after the last dose of study treatment.

14. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy:

    • Anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter.

    Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2).

    • 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/ or https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).

    • 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.

15. Evidence of ongoing alcohol or drug abuse as assessed by the investigator.
16. Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study.

Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A)

Inclusion:

In general, the SmPC of the respective combination drug should be consulted for instructions/restrictions with respect to interactions with concomitant medications.

1. PIK3CA mutation by local laboratory assessment.
2. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with alpelisib or any other PI3K inhibitor.
2. 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%).
3. Known intolerance to alpelisib or any of its excipients.
4. 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
5. 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 up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with everolimus.
2. Known intolerance to everolimus or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is exclusionary if the patient relapsed within the past 12 months.
2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy with ribociclib is also exclusionary if the patient relapsed within the past 12 months.
2. Known intolerance to ribociclib or any of its excipients.
3. QTcF values ≥450 msec.

4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:

   • Long QT syndrome
   • Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
   • Electrolyte abnormalities
5. 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. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with palbociclib in the metastatic setting.
2. Known intolerance to palbociclib or any of its excipients

Additional Eligibility for the Palbociclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

1. Prior therapy with a CDK4/6i in the metastatic setting.
2. Known intolerance to palbociclib or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

1. Prior therapy with any CDK4/6i in the metastatic setting.
2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for Ribociclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

1. Prior therapy with a CDK4/6i in the advanced or metastatic setting.
2. Known intolerance to ribociclib or any of its excipients.
3. QTcF values ≥450 msec.

4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:

   • Long QT syndrome
   • Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
   • Electrolyte abnormalities
5. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Stemline Trials; 718-509-3742; trials@stemline.com

Contact: Mary Ann Samparani; 646-731-2146; msamparani@stemline.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05563220
• Other Study ID Numbers: STML-ELA-0222
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Stemline Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Stemline Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Stemline Therapeutics, Inc.
• Verification Date: April 2024