Breast Cancer
Conditions
Brief summary
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.
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.
Interventions
Pharmaceutical form: Capsules, Route of administration: Oral
DRUGLetrozole
Pharmaceutical form: Tablets, Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Ki67 Level at Day 15 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15 | Baseline, 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. |
| Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15 | Baseline, 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. |
| Number of Participants With Abnormalities: Hematological Parameters | From first dose of study drug up to Day 14 | 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. |
| Number of Participants With Abnormalities: Clinical Chemistry | From first dose of study drug up to Day 14 | 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. |
Countries
Belgium, France, Italy, Japan, Puerto Rico, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 32 active sites in 8 countries. A total of 135 participants were screened from 04-February-2020 to 21-April-2021, of which 30 participants were screen failures mainly due to selection criteria not met.
Pre-assignment details
A total of 105 participants with early breast cancer were randomized in 1:1:1 ratio to receive treatment with amcenestrant 400 milligrams (mg), amcenestrant 200 mg, or letrozole 2.5 mg.
Participants by arm
| Arm | Count |
|---|---|
| Amcenestrant 400 mg Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14. | 34 |
| Amcenestrant 200 mg Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14. | 36 |
| Letrozole 2.5 mg Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14. | 35 |
| Total Title | 105 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Amcenestrant 400 mg | Total Title | Letrozole 2.5 mg | Amcenestrant 200 mg |
|---|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 8.6 | 63.2 years STANDARD_DEVIATION 8.4 | 63.7 years STANDARD_DEVIATION 8.5 | 63.4 years STANDARD_DEVIATION 8.4 |
| Ki67 expression at Baseline | 33.8 percentage of positive tumor cells STANDARD_DEVIATION 16.3 | 32.5 percentage of positive tumor cells STANDARD_DEVIATION 16.3 | 32.6 percentage of positive tumor cells STANDARD_DEVIATION 18.5 | 31.2 percentage of positive tumor cells STANDARD_DEVIATION 14.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 10 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 20 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) White | 23 Participants | 72 Participants | 25 Participants | 24 Participants |
| Sex: Female, Male Female | 34 Participants | 105 Participants | 35 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 36 | 0 / 35 |
| other Total, other adverse events | 11 / 33 | 12 / 36 | 14 / 35 |
| serious Total, serious adverse events | 0 / 33 | 2 / 36 | 0 / 35 |
Outcome results
Primary
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.
Time frame: Baseline, Day 15
Population: Analysis was performed on modified intent-to-treat (mITT) population that included all enrolled participants for whom there was a confirmation of successful allocation of a randomization number by IRT, who had taken at least one study drug, and who had both Baseline and post treatment available biopsies with Ki67 values.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Amcenestrant 400 mg | Percent Change From Baseline in Ki67 Level at Day 15 | 75.9 percent change |
| Amcenestrant 200 mg | Percent Change From Baseline in Ki67 Level at Day 15 | 68.2 percent change |
| Letrozole 2.5 mg | Percent Change From Baseline in Ki67 Level at Day 15 | 77.7 percent change |
Comparison: Geometric LS-means ratio of proportional change was the ratio of geometric LS-means of the proportional change between groups (Amcenestrant 400 mg versus Letrozole 2.5 mg).95% CI: [0.72, 1.63]
Comparison: Geometric LS-means ratio of proportional change was the ratio of geometric LS-means of the proportional change between groups (Amcenestrant 200 mg versus Letrozole 2.5 mg).95% CI: [0.95, 2.12]
Secondary
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.
Time frame: Baseline, Day 15
Population: Analysis was performed on mITT population. Here, 'overall number of participants analyzed' signifies participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Amcenestrant 400 mg | Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15 | -176.7 score on a scale |
| Amcenestrant 200 mg | Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15 | -202.9 score on a scale |
| Letrozole 2.5 mg | Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15 | -32.5 score on a scale |
Secondary
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.
Time frame: From first dose of study drug up to Day 14
Population: Analysis was performed on safety population. Here, 'Number analyzed' signifies participants with available data for each specified category for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypernatremia (sodium increased) | 1 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyponatremia (sodium decreased) | 0 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyperkalemia (potassium increased) | 2 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypokalemia (potassium decreased) | 0 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Creatinine increased | 0 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypoglycemia (glucose decreased) | 0 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypoglycemia (glucose decreased) | 1 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypernatremia (sodium increased) | 1 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypokalemia (potassium decreased) | 2 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Creatinine increased | 3 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyponatremia (sodium decreased) | 1 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyperkalemia (potassium increased) | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyponatremia (sodium decreased) | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hyperkalemia (potassium increased) | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypoglycemia (glucose decreased) | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypokalemia (potassium decreased) | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Hypernatremia (sodium increased) | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Clinical Chemistry | Creatinine increased | 2 Participants |
Secondary
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.
Time frame: From first dose of study drug up to Day 14
Population: Analysis was performed on safety population that included all participants who were randomly assigned to study drug and who took at least 1 dose of study drug. Here, 'Number analyzed' signifies participants with available data for each specified category for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Lymphocyte count decreased | 1 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | White blood cell decreased | 5 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Neutrophil count decreased | 1 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Anemia (hemoglobin decreased) | 6 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Hemoglobin increased | 0 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Platelet count decreased | 1 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | INR increased | 0 Participants |
| Amcenestrant 400 mg | Number of Participants With Abnormalities: Hematological Parameters | Eosinophilia (eosinophils increased) | 2 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Neutrophil count decreased | 0 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Anemia (hemoglobin decreased) | 4 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Eosinophilia (eosinophils increased) | 1 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Hemoglobin increased | 0 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Platelet count decreased | 1 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | Lymphocyte count decreased | 3 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | White blood cell decreased | 6 Participants |
| Amcenestrant 200 mg | Number of Participants With Abnormalities: Hematological Parameters | INR increased | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Neutrophil count decreased | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | INR increased | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | White blood cell decreased | 3 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Anemia (hemoglobin decreased) | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Lymphocyte count decreased | 1 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Platelet count decreased | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Hemoglobin increased | 0 Participants |
| Letrozole 2.5 mg | Number of Participants With Abnormalities: Hematological Parameters | Eosinophilia (eosinophils increased) | 1 Participants |
Secondary
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.
Time frame: Baseline, Day 15
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amcenestrant 400 mg | Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15 | 74.2 percentage of participants |
| Amcenestrant 200 mg | Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15 | 68.6 percentage of participants |
| Letrozole 2.5 mg | Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15 | 89.7 percentage of participants |