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)

• ClinicalTrials.gov Identifier: NCT04191382
• Recruitment Status: Terminated
• First Posted: December 9, 2019
• Results First Posted: June 29, 2022
• Last Update Posted: June 29, 2022
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Amcenestrant (SAR439859); Drug: Letrozole
• Enrollment: 105

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.

Arm/Group Title	Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description	Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Period Title: Overall Study
Started [1]	34	36	35
Treated	33	36	35
Completed	33	36	35
Not Completed	1	0	0
Reason Not Completed
Withdrawal by Subject	1	0	0
[1] Randomized

Baseline Characteristics

Arm/Group Title		Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg	Total Title
Arm/Group Description		Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.	[Not Specified]
Overall Number of Baseline Participants		34	36	35	105
Baseline Analysis Population Description		Analysis was performed on intent-to-treat (ITT) population that included all enrolled participants for whom there was a confirmation of successful allocation of a randomization number by interactive response technology (IRT) and were analyzed according to the treatment arm assigned at randomization.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	34 participants	36 participants	35 participants	105 participants
		62.4 (8.6)	63.4 (8.4)	63.7 (8.5)	63.2 (8.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	34 participants	36 participants	35 participants	105 participants
	Female	34 100.0%	36 100.0%	35 100.0%	105 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	34 participants	36 participants	35 participants	105 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	2 5.9%	3 8.3%	5 14.3%	10 9.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 2.9%	0 0.0%	0 0.0%	1 1.0%
	White	23 67.6%	24 66.7%	25 71.4%	72 68.6%
	More than one race	0 0.0%	1 2.8%	1 2.9%	2 1.9%
	Unknown or Not Reported	8 23.5%	8 22.2%	4 11.4%	20 19.0%
Ki67 expression at Baseline [1] [2]; Mean (Standard Deviation); Unit of measure: Percentage of positive tumor cells
	Number Analyzed	32 participants	36 participants	32 participants	100 participants
		33.8 (16.3)	31.2 (14.3)	32.6 (18.5)	32.5 (16.3)
		[1] Measure Description: Tumor tissue collected through a core-cut biopsy at Baseline was used to determine Ki67 expression. Ki67 expression was defined as the percentage of positive tumor cells assessed by central reading.; [2] Measure Analysis Population Description: Here, 'Number analyzed' signifies participants with available data at Baseline for the specified Baseline measure.

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Ki67 Level at Day 15
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description:	Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Overall Number of Participants Analyzed	31	35	29
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	75.9; (67.9 to 81.9)	68.2; (58.4 to 75.7)	77.7; (70.0 to 83.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amcenestrant 400 mg, Letrozole 2.5 mg
	Comments	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).
	Type of Statistical Test	Other
	Comments	Other descriptive analysis
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.63
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Amcenestrant 200 mg, Letrozole 2.5 mg
	Comments	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).
	Type of Statistical Test	Other
	Comments	Other descriptive analysis
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 0.95 to 2.12
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Participants With Percent Change From Baseline in Ki67 Greater Than or Equal to (>=) 50 Percent at Day 15
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description:	Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Overall Number of Participants Analyzed	31	35	29
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	74.2; (55.4 to 88.1)	68.6; (50.7 to 83.1)	89.7; (72.6 to 97.8)

3. Secondary Outcome

Title	Change From Baseline in Estrogen Receptor (ER) Expression as Measured by H-Score at Day 15
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population. Here, 'overall number of participants analyzed' signifies participants with available data for this outcome measure.

Arm/Group Title	Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description:	Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Overall Number of Participants Analyzed	28	32	28
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-176.7; (-201.4 to -152.0)	-202.9; (-226.1 to -179.7)	-32.5; (-57.2 to -7.7)

4. Secondary Outcome

Title	Number of Participants With Abnormalities: Hematological Parameters
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title		Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description:		Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Overall Number of Participants Analyzed		33	36	35
Measure Type: Count of Participants; Unit of Measure: Participants
White blood cell decreased	Number Analyzed	32 participants	35 participants	35 participants
		5 15.6%	6 17.1%	3 8.6%
Neutrophil count decreased	Number Analyzed	32 participants	35 participants	35 participants
		1 3.1%	0 0.0%	1 2.9%
Anemia (hemoglobin decreased)	Number Analyzed	32 participants	35 participants	35 participants
		6 18.8%	4 11.4%	1 2.9%
Hemoglobin increased	Number Analyzed	32 participants	35 participants	35 participants
		0 0.0%	0 0.0%	0 0.0%
Platelet count decreased	Number Analyzed	32 participants	35 participants	35 participants
		1 3.1%	1 2.9%	0 0.0%
Lymphocyte count decreased	Number Analyzed	32 participants	35 participants	35 participants
		1 3.1%	3 8.6%	1 2.9%
INR increased	Number Analyzed	28 participants	28 participants	31 participants
		0 0.0%	0 0.0%	0 0.0%
Eosinophilia (eosinophils increased)	Number Analyzed	32 participants	35 participants	35 participants
		2 6.3%	1 2.9%	1 2.9%

5. Secondary Outcome

Title	Number of Participants With Abnormalities: Clinical Chemistry
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population. Here, 'Number analyzed' signifies participants with available data for each specified category for this outcome measure.

Arm/Group Title		Amcenestrant 400 mg	Amcenestrant 200 mg	Letrozole 2.5 mg
Arm/Group Description:		Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.	Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.	Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
Overall Number of Participants Analyzed		33	36	35
Measure Type: Count of Participants; Unit of Measure: Participants
Hypernatremia (sodium increased)	Number Analyzed	32 participants	35 participants	35 participants
		1 3.1%	1 2.9%	1 2.9%
Hyponatremia (sodium decreased)	Number Analyzed	32 participants	35 participants	35 participants
		0 0.0%	1 2.9%	0 0.0%
Hyperkalemia (potassium increased)	Number Analyzed	32 participants	35 participants	35 participants
		2 6.3%	1 2.9%	1 2.9%
Hypokalemia (potassium decreased)	Number Analyzed	32 participants	35 participants	35 participants
		0 0.0%	2 5.7%	0 0.0%
Creatinine increased	Number Analyzed	32 participants	34 participants	35 participants
		0 0.0%	3 8.8%	2 5.7%
Hypoglycemia (glucose decreased)	Number Analyzed	32 participants	35 participants	35 participants
		0 0.0%	1 2.9%	0 0.0%

Adverse Events

Time Frame	From first dose up to 30 days following the last dose of study drug (up to 45 days)
Adverse Event Reporting Description	Reported adverse events (AEs) are treatment-emergent adverse events (TEAEs) i.e., AEs that developed, worsened, or became serious during the treatment period (time from the first dose of study drug up to 30 days after last dose of study drug). Analysis was performed on safety population.
Arm/Group Title	Amcenestrant 400 mg		Amcenestrant 200 mg		Letrozole 2.5 mg
Arm/Group Description	Participants received 4 capsules of 100 mg of amcenestrant once daily (QD) from Day 1 to Day 14.		Participants received 2 capsules of 100 mg of amcenestrant QD from Day 1 to Day 14.		Participants received 2.5 mg of letrozole tablet QD from Day 1 to Day 14.
All-Cause Mortality
	Amcenestrant 400 mg		Amcenestrant 200 mg		Letrozole 2.5 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/33 (0.00%)		0/36 (0.00%)		0/35 (0.00%)
Serious Adverse Events
	Amcenestrant 400 mg		Amcenestrant 200 mg		Letrozole 2.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0.00%)		2/36 (5.56%)		0/35 (0.00%)
Infections and infestations
Pneumonia † 1	0/33 (0.00%)	0	1/36 (2.78%)	1	0/35 (0.00%)	0
Wound Infection † 1	0/33 (0.00%)	0	1/36 (2.78%)	1	0/35 (0.00%)	0
1 Term from vocabulary, MedDRA24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Amcenestrant 400 mg		Amcenestrant 200 mg		Letrozole 2.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/33 (33.33%)		12/36 (33.33%)		14/35 (40.00%)
Gastrointestinal disorders
Constipation † 1	1/33 (3.03%)	1	2/36 (5.56%)	2	1/35 (2.86%)	1
Diarrhoea † 1	0/33 (0.00%)	0	3/36 (8.33%)	3	3/35 (8.57%)	3
General disorders
Asthenia † 1	2/33 (6.06%)	2	2/36 (5.56%)	2	0/35 (0.00%)	0
Fatigue † 1	2/33 (6.06%)	2	1/36 (2.78%)	1	1/35 (2.86%)	1
Feeling Cold † 1	2/33 (6.06%)	2	0/36 (0.00%)	0	0/35 (0.00%)	0
Injury, poisoning and procedural complications
Procedural Pain † 1	2/33 (6.06%)	2	1/36 (2.78%)	1	2/35 (5.71%)	2
Investigations
Alanine Aminotransferase Increased † 1	1/33 (3.03%)	1	2/36 (5.56%)	2	0/35 (0.00%)	0
Metabolism and nutrition disorders
Decreased Appetite † 1	2/33 (6.06%)	2	1/36 (2.78%)	1	0/35 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/33 (6.06%)	2	0/36 (0.00%)	0	3/35 (8.57%)	3
Nervous system disorders
Headache † 1	3/33 (9.09%)	3	0/36 (0.00%)	0	2/35 (5.71%)	2
Psychiatric disorders
Anxiety † 1	1/33 (3.03%)	1	2/36 (5.56%)	2	0/35 (0.00%)	0
Insomnia † 1	4/33 (12.12%)	4	1/36 (2.78%)	1	0/35 (0.00%)	0
Reproductive system and breast disorders
Breast Pain † 1	1/33 (3.03%)	1	0/36 (0.00%)	0	3/35 (8.57%)	3
Vascular disorders
Hot Flush † 1	4/33 (12.12%)	4	1/36 (2.78%)	1	5/35 (14.29%)	5
1 Term from vocabulary, MedDRA24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The study recruitment discontinued early based on strategic sponsor decision that was not driven by any safety concerns. No inferential statistical analysis was performed due to early termination.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement
• Phone: 800-633-1610 ext 6#
• EMail: Contact-US@sanofi.com

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT04191382
• Other Study ID Numbers: ACT16106; 2019-002015-26 ( EudraCT Number ); U1111-1228-9473 ( Other Identifier: UTN )
• First Submitted: December 5, 2019
• First Posted: December 9, 2019
• Results First Submitted: May 27, 2022
• Results First Posted: June 29, 2022
• Last Update Posted: June 29, 2022