Phase 2 Window Study of SAR439859 (Amcenestrant) Versus Letrozole in Post-menopausal Patients With ER+, HER2- Pre-operative Post-menopausal Primary Breast Cancer (AMEERA-4)

Phase 2 Window Study of Two Dose Levels of Amcenestrant [SAR439859] (SERD) Versus Letrozole in Newly Diagnosed Pre-operative Post-menopausal Patients With ER Positive, HER2 Negative Primary Breast Cancer

Primary Objective:

To determine whether amcenestrant given at 2 different doses improved the antiproliferative activity when compared to letrozole.

Secondary Objectives:

• To assess the proportion of participants with a relative decrease from Baseline in percentage of positive tumor cells tested by immunohistochemistry greater than or equal to (>=) 50 percent (%) (Ki67 >=50%) in the three treatment arms.
• To assess estrogen receptor (ER) degradation in biopsies in participants in the three treatment arms.
• To assess safety in the three treatment arms.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Amcenestrant (SAR439859); Drug: Letrozole

Detailed Description

Duration of the study, per participant, would include screening period of up to 14 days before randomization, treatment period of 14 days and post-treatment safety follow-up period of 30±7 days after last investigational medicinal product (IMP) intake.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Investigational Site Number 0560001
  • Namur, Belgium, 5000
    • Investigational Site Number 0560002
• France
  • Nantes, France, 44093
    • Investigational Site Number 2500001
  • Paris, France, 75010
    • Investigational Site Number 2500004
  • Saint Cloud, France, 92210
    • Investigational Site Number 2500002
  • Toulouse Cedex 9, France, 31059
    • Investigational Site Number 2500003
• Italy
  • Meldola, Italy, 47014
    • Investigational site number 3800004
  • Milano, Italy, 20132
    • Investigational Site Number 3800002
  • Milano, Italy, 20141
    • Investigational Site Number 3800001
• Japan
  • Osaka-Shi, Japan
    • Investigational Site Number 3920002
  • Sapporo-Shi, Japan
    • Investigational Site Number 3920003
  • Yokohama-Shi, Japan
    • Investigational Site Number 3920001
• Puerto Rico
  • Hato Rey, Puerto Rico, 00917
    • Investigational Site Number 8400007
• Russian Federation
  • Moscow, Russian Federation, 117186
    • Investigational Site Number 6430006
  • Moscow, Russian Federation, 119991
    • Investigational Site Number 6430004
  • Saint -Petersburg, Russian Federation, 197758
    • Investigational Site Number 6430002
  • Saint-Petersburg, Russian Federation, 194156
    • Investigational Site Number 6430003
  • St.Petersburg, Russian Federation, 195271
    • Investigational Site Number 6430007
• Spain
  • Barcelona, Spain, 08003
    • Investigational Site Number 7240005
  • Córdoba, Spain, 14004
    • Investigational Site Number 7240003
  • Madrid, Spain, 28041
    • Investigational Site Number 7240001
  • Valencia / Valencia, Spain, 46010
    • Investigational Site Number 7240002
• Ukraine
  • Kharkiv, Ukraine, 61166
    • Investigational Site Number 8040004
  • Uzhgorod, Ukraine, 88000
    • Investigational Site Number 8040001
  • Vinnytsia, Ukraine, 21029
    • Investigational Site Number 8040002
  • Zaporizhzhya, Ukraine, 69040
    • Investigational Site Number 8040005
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Investigational Site Number 8400014
  • California
    • Los Angeles, California, United States, 90095
      • Investigational Site Number 8400010
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Investigational Site Number 8400018
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Investigational Site Number 8400005
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Investigational Site Number 8400016
  • Washington
    • Tacoma, Washington, United States, 98405
      • Investigational Site Number 8400012

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion criteria :

• Histological or cytological proven diagnosis of invasive breast adenocarcinoma.
• Localized breast cancer eligible for upfront breast conservative surgery or upfront mastectomy: Stage I, Stage II or operable Stage III (excluded T4) as defined in American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th edition 2017.
• Postmenopausal women as defined by one of the following:
• Spontaneous cessation of menses greater than (>) 12 months.
• or who had received hormonal replacement therapy but had discontinued the treatment and had follicle stimulating hormone (FSH) level in the postmenopausal range.
• or with status post bilateral surgical oophorectomy.
• or post bilateral ovarian ablation through pelvic radiotherapy.
• Breast tumor size of at least 10 millimeters (mm) in greatest dimension measured by ultrasound.
• Primary tumor had to be positive for Estrogen Receptors (ER+) and negative for HER2 (HER2-) receptor by immunohistochemistry.
• Ki67 level of at least 15% at diagnosis from immunohistochemistry of the tumor.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Exclusion criteria:

• Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of SAR439859 or letrozole.
• Participants unable to swallow normally and to take capsules or tablets.
• Participants with known active hepatitis A, B, C infection; or hepatic cirrhosis.
• Participant with any other cancer; adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or any other cancer from which the participant had been disease free for >3 years were allowed.
• Evidence of metastatic spread by standard assessment according to local practice.
• Treatment with strong Cytochrome P450 3A (CYP3A) inducers or drugs that had the potential to inhibit uridine diphosphate glucuronosyltransferase (UGT) within 2 weeks before first study treatment administration or 5 elimination half-lives whichever was longest.
• Treatment with drugs that were sensitive substrates of P-glycoprotein (P-gp) or of breast cancer resistance protein (BCRP) within 2 weeks before first study treatment administration or 5 elimination half-lives whichever was longer.
• Use of any investigational agent within 4 weeks prior to randomization.
• Recent use of hormone replacement therapy (last dose less than or equal to [<=] 30 days prior to randomization).
• Prior anti-cancer treatment was not allowed unless it was then completed at least 1 year prior to inclusion into this trial.
• Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments).
• Inadequate hematological or renal function.
• Prothrombin time/international normalized ratio (INR) >1.5 * upper limit of normal (ULN) or outside therapeutic range if received anticoagulation that would have had affected the prothrombin time/INR.
• Any of the following abnormal liver function test results: Aspartate aminotransferase >1.5 * ULN; Alanine aminotransferase >1.5 * ULN; Total bilirubin >1.5 * ULN.
• Participants were employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amcenestrant 400 mg; Participants received 4 capsules of 100 milligrams (mg) of amcenestrant once daily (QD) from Day 1 to Day 14.	Drug: Amcenestrant (SAR439859); Pharmaceutical form: Capsules, Route of administration: Oral
Experimental: Amcenestrant 200 mg; Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Drug: Amcenestrant (SAR439859); Pharmaceutical form: Capsules, Route of administration: Oral
Active Comparator: Letrozole 2.5 mg; Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.	Drug: Letrozole; Pharmaceutical form: Tablets, Route of administration: Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Ki67 Level at Day 15	Tumor tissue collected through a core-cut biopsy at Baseline and Day 15 was used to determine Ki67 expression. Ki67 expression was defined as the percentage of positive tumor cells assessed by central reading. Ki67 percent change from Baseline for a given participant was defined as 100*(Ki67pre - Ki67post) / Ki67pre, where Ki67pre and Ki67post were pre-treatment and post-treatment Ki67 value of the participant. Adjusted geometric least square (LS) means and 95 percentage (%) confidence interval (CI) for the percent change were obtained from analysis of covariance (ANCOVA) model of the log proportional change i.e., log (Ki67post/ki67pre) with treatment and log-Ki67pre as fixed effect and converted by antilog transformation.	Baseline, Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15	Tumor tissue collected through a core-cut biopsy at Baseline and Day 15 was used to determine Ki67 expression. Ki67 expression was defined as the percentage of positive tumor cells assessed by central reading. Ki67 percent change from Baseline for a given participant was defined as 100*(Ki67pre - Ki67post) / Ki67pre, where Ki67pre and Ki67post were pre-treatment and post-treatment Ki67 value of the participant.	Baseline, Day 15
Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15	Change from Baseline in ER expression was measured by H-Score. The H-score was calculated as the sum of the percent of cells staining positive (0 to 100) multiplied staining intensity level from 0 to 3 (0=none, 1=low, 2=moderate, 3=high). Total ER expression H-score ranged from 0 to 300, where higher score indicated stronger ER expression. Change from Baseline in H-Score equals H-scorepost minus H-scorepre; where H-scorepost and H-scorepre denoted post-treatment and pre-treatment H-scores, respectively. LS-means and 95% CI were obtained from an ANCOVA model for change from baseline with treatment and baseline as fixed effect.	Baseline, Day 15
Number of Participants With Abnormalities: Hematological Parameters	Hematology parameters covered by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and included: Hemoglobin, Lymphocyte, Neutrophils, Leukocytes (white blood cells), Anemia, Platelets, Eosinophils, and international normalized ratio (INR). An NCI-CTCAE Grades 1 to 5 were described as: Grade 1-Mild; asymptomatic/mild symptoms; Grade 2-Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental daily activities. Grade 3-Severe/medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4-Life-threatening consequences; Grade 5-Death. Data for 'All Grades' were reported in this outcome measure.	From first dose of study drug up to Day 14
Number of Participants With Abnormalities: Clinical Chemistry	Clinical chemistry laboratory parameters covered by NCI-CTCAE and included: Glucose, Potassium, Sodium, Creatinine. An NCI-CTCAE Grades 1 to 5 were described as: Grade 1-Mild; asymptomatic or mild symptoms; Grade 2- Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental daily activities; Grade 3-Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4-Life-threatening consequences; Grade 5-Death. Data for 'All Grades' were reported in this outcome measure.	From first dose of study drug up to Day 14

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2020
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): May 28, 2021

Study Registration Dates

• First Submitted: December 5, 2019
• First Submitted That Met QC Criteria: December 5, 2019
• First Posted (Actual): December 9, 2019

Study Record Updates

• Last Update Posted (Actual): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 27, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: ACT16106; 2019-002015-26 (EudraCT Number); U1111-1228-9473 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No