Elacestrant in Preoperative Setting, a Window of Opportunity Study (ELIPSE)

ELIPSE is a window of opportunity, prospective, multicenter, phase 0 trial which evaluates the effect of Elacestrant on proliferation after 4 weeks of treatment in postmenopausal women with Estrogen Receptor-positive (ER+) and Human Epidermal Growth Factor Receptor 2-negative (HER2-negative) early breast cancer (BC) amenable to surgery.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Hormone Receptor Positive Breast Carcinoma
• Intervention / Treatment: Drug: Elacestrant

Detailed Description

The main hypothesis is that Elacestrant induces a significant proliferative arrest (Ki67 ≤ 2.7%) in ER+ and HER2-negative BC naïve to Endocrine Therapy (ET). To test this hypothesis, a total of 24 patients will be recruited.

Secondary objectives will include correlative molecular and histological analyses at the tumor tissue, changes in Ki67 and the identification of molecular biomarkers and gene signatures of response to Elacestrant. Molecular analysis of tumor circulating DNA (ctDNA) in blood will be also performed.

The study population consists of postmenopausal women with cT1c-3 (minimal 15 mm of largest diameter) cN0 cM0, ER+ and HER2-negative breast operable tumors.

Patients who fulfil all eligibility criteria will then start treatment in Elacestrant monotherapy cohort as follows: Elacestrant continuously at 400 mg given orally (PO), once a day, in a continuous schedule (QD). After 4 weeks (+/- 2 days) of Elacestrant treatment, surgery will be performed in accordance to local practice. If the tumor is not surgically removed after 4 weeks (+/-3 days), a tumor biopsy will be obtained. In this case, patients may continue further neoadjuvant treatment under physicians' criteria.

Two biopsies of the same lesion will be mandatory: first the screening sample and second the surgical sample. A core biopsy will be collected if surgery is not performed for any reason. Complete Cell Cycle Arrest (CCCA) (determined by Ki67 ≤ 2.7%) and relative changes in the PAM50 subtypes in tumor samples will be analyzed at baseline and after 4-weeks of Elacestrant therapy at central laboratory. Ki67 status at baseline will be performed at local sites for inclusion criteria (Ki67 at diagnostic ≥10%). Extensive RNA-based and blood analyses will be performed in tumor specimens at the same timepoints.

Safety assessments will include the incidence, nature, and severity of Adverse Events (AEs) and laboratory abnormalities graded per the NCI CTCAE v.5.0

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08036
    • Hospital Clinic Barcelona
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • ICO Badalona
    • Sant Cugat Del Vallès, Barcelona, Spain, 08195
      • Hospital General de Catalunya

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Written and signed informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
2. Age ≥ 18 years.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

4. Postmenopausal women defined either by:

   1. Age ≥60,
   2. Age < 60 and amenorrhea for ≥ 12 months and FSH and E2 plasmatic levels in the post-menopausal range per local standards or
   3. Prior bilateral oophorectomy (≥ 30 days before Day 1 of the study treatment).

5. Histologically confirmed invasive breast carcinoma eligible for surgery with all the following characteristics:

   1. Primary tumor diameter of at least 15 mm (cT1c-3) as measured by breast US.
   2. No regional lymph node metastases by imaging or clinical examination (cN0).
   3. ER+ tumors, irrespective of PgR status, (nuclear stain >1%) as assessed locally, defined by the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice guidelines.
   4. HER2-negative status, as assessed locally, defined by the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
   5. In case of multifocal tumors (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be measured in at least one dimension of minimal 15 mm per US. This lesion will be designated as 'target' lesion for all subsequent evaluations. ER+ and HER2-negative status must be documented in all the tumor foci if they are independent of the target lesion (does not apply to small tumoral foci around the main lesion).
   6. Cells staining positive for Ki67 ≥ 10% as locally assessed.
   7. Available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor specimen or possibility to obtain one. Minimal sample requirements are: at least 2 tumor cylinders with a minimal tissue surface of 10 mm2, containing ≥10% tumor cells, enough to obtain at least 2 cuts of 10 μm each. Tumor cylinder will be mandatory.
6. No clinical or radiographic evidence of distant metastases (M0).

7. Adequate hematologic and organ function within 14 days before the first study treatment on Day 1, defined by the following:

   1. Neutrophils (ANC ≥1500/μL).
   2. Hemoglobin ≥9 g/dL (with no need for transfusions).
   3. Platelet count ≥100000/μL.
   4. Serum albumin ≥3 g/dL.

   5. Calculated creatinine clearance of ≥60 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation:

      (140 - age) x (weight in kg) x 0.85 72 x (serum creatinine in mg/dL)

   6. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) within therapeutic range. History of deep thrombotic episodes or pulmonary embolism, or incremental risk for thrombosis at investigator criteria.
   7. Potassium, total Calcium (corrected for serum albumin), and Sodium with institutional normal limits or corrected with normal limits with supplement before first dose of study medication.
8. Ability to swallow study drug and comply with study requirements.
9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion Criteria:

1. Inoperable locally advanced or inflammatory breast cancer.
2. Metastatic (Stage IV) breast cancer.
3. Synchronous invasive bilateral or multicentric breast cancer.
4. Patients requiring immediate neoadjuvant chemotherapy or immediate surgical intervention.
5. Patients who have undergone sentinel lymph node biopsy or tumor excisional biopsy prior to study treatment.
6. Prior malignancy within 3 years prior to randomization, except curatively treated non-melanoma skin cancer, in situ cervical cancer or adequately treated Stage I or II cancer from which the patient is currently in complete remission or other cancer from which the patient has been disease-free for 2 years.
7. Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula (QTcF) > 480 milliseconds or any clinically significant cardiac rhythm abnormalities.

8. Liver function tests documented within the screening period and on Day 1 of treatment period:

   1. Total bilirubin >1.5x the upper limit of normal unless the patient has documented non-malignant disease (e.g. Gilbert´s syndrome) for whom conjugated bilirubin must be under ULN.
   2. AST and ALT >2.5x ULN.
   3. Alkaline phosphatase ALP >2x ULN.
9. Concurrent, serious, uncontrolled infections or current known infection with HIV (testing is not mandatory).
10. Known hypersensitivity to any of the study drugs, including excipients.
11. History or clinical evidence of any liver or biliary pathology including cirrhosis, infectious disease, inflammatory conditions, steatosis, or cholangitis (including ascending cholangitis, primary sclerosing cholangitis, obstruction, perforation, fistula of biliary tract, spasm of sphincter of Oddi, biliary cyst or biliary atresia).

12. Known clinically significant history active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis.

    • Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [HBcAg] antibody test) are eligible.
    • Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
13. Chronic adrenal failure or is receiving concurrent long-term corticosteroid therapy. The following corticosteroid uses are permitted: single doses, topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airway diseases), eye drops or local injections (e.g. intra-articular).
14. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to swallow pills.
15. History of or clinical evidence of significant co-morbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent.
16. Received an investigational product or been treated with an investigational device within 30 days prior to first drug administration or plans to start any other investigational product or device study within 30 days after last drug administration.
17. Previous hormonal treatments for other indications such as osteoporosis, breast cancer prevention, hormonal substitutive therapy, such as raloxifen, tamoxifen, estrogen, progestins must have ended at least 24 months prior to trial registration. If a patient is on natural products known to contain progestins, they must be stopped 14 days prior to beginning study treatment.
18. Used any prescription medication during the prior 1 month that the investigator judges is likely to interfere with the study or to pose an additional risk to the patient in participating.
19. Major surgical procedure or significant traumatic injury within 30 days prior to enrollment.
20. Patients with thromboembolic risks.
21. Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Elacestrant; 400 mg given orally (PO), once a day, in a continuous schedule (QD). 4 weeks (+/- 2 days) of elacestrant treatment	Drug: Elacestrant; Elacestrant continuously at 400 mg given orally (PO), once a day, in a continuous schedule (QD) for 4 weeks (+/- 2 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Cell Cycle Arrest	Ki67 ≤ 2.7%	After 4 weeks (+/- 2 days) of elacestrant therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAM50 (Prediction Analysis of Microarray 50) subtype change	PAM50 subtype changes upon elacestrant therapy	After 4 weeks (+/- 2 days) of elacestrant therapy
Gene expression change (post-treatment/pre-treatment)	Differential expression (mean suppression = 100 - [geometric mean (post-treatment / pre-treatment · 100)]) of 11 proliferative genes from PAM50 (BIRC5, CCNB1, CDC20, CDCA1, CEP55, KNTC2, MKI67, PTTG1, RRM2, TYMS and UBE2C).	After 4 weeks (+/- 2 days) of elacestrant therapy
Adverse Events	Frequency and severity of adverse events (evaluated according to CTCAE v.5.0.) and frequency of interruptions due to treatment toxicity.	Until End of Study Visit (7-28 days after surgery)
Global gene expression changes	Relative changes of expression 770 genes across of 23 categories of BC tumor biology after 4 weeks of treatment. This study will be performed using the Nanostring nCounter Breast 360TM panel	After 4 weeks (+/- 2 days) of elacestrant therapy
Gene expression-based signature of response	To derive a new gene expression-based signature of response to Elacestrant.	After 4 weeks (+/- 2 days) of elacestrant therapy
Celularity/Tumor Infiltrating Lymphocytes (CelTIL) score	CelTIL score = -0.8 × tumor cellularity (in %) + 1.3 × TILs (in %). The minimum and maximum unscaled CelTIL scores will be -80 and 130. This unscaled CelTIL score will then be scaled to reflect a range from 0 to 100 points. TILs determination will be quantified according to the 2014 Guidelines developed by the International TILs Working Group	After 4 weeks (+/- 2 days) of elacestrant therapy
Mean change in Ki67	Mean change in Ki67 values per central assessment before and after therapy and its 95% confidence interval (CI).	After 4 weeks (+/- 2 days) of elacestrant therapy
Changes in the distribution of somatic mutations	To identify changes in the distribution of somatic mutations (e.g. PIK3CA, ESR1) between basal and surgery samples	After 4 weeks (+/- 2 days) of elacestrant therapy
ctDNA (post-treatment/pre-treatment)	Quantification of ctDNA (post-treatment/pre-treatment)	After 4 weeks (+/- 2 days) of elacestrant therapy

Collaborators and Investigators

• Sponsor: SOLTI Breast Cancer Research Group
• Collaborators: Radius Health, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2021
• Primary Completion (Actual): February 8, 2022
• Study Completion (Actual): February 25, 2022

Study Registration Dates

• First Submitted: March 12, 2021
• First Submitted That Met QC Criteria: March 12, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 25, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: ELIPSE (SOLTI-1905)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes