Amcenestrant (SAR439859) Plus Palbociclib as First Line Therapy for Patients With ER (+) HER2(-) Advanced Breast Cancer

Study Overview
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Brief Summary
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Primary Objective: To determine whether Amcenestrant (SAR439859) in combination with palbociclib improves progression free survival (PFS) when compared with letrozole in combination with palbociclib in participants with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received any prior systemic anticancer therapies for advanced disease. Secondary Objective: To compare the overall survival in both treatment arms. To evaluate the objective response rate in both treatment arms. To evaluate the duration of response in both treatment arms. To evaluate the clinical benefit rate in both treatment arms. To evaluate progression-free survival on next line of therapy. To evaluate the pharmacokinetics of amcenestrant, and palbociclib. To evaluate health-related quality of life in both treatment arms. To evaluate the time to first chemotherapy in both treatment arms. To evaluate safety in both treatment arms.

Detailed Description
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Study duration per participant was approximately 59 months, which includes a 33- month treatment period.

Official Title
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A Randomized, Multicenter, Double-blind Phase 3 Study of Amcenestrant (SAR439859) Plus Palbociclib Versus Letrozole Plus Palbociclib for the Treatment of Patients With ER (+), HER2 (-) Breast Cancer Who Have Not Received Prior Systemic Anti-cancer Treatment for Advanced Disease

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Amcenestrant-matching placebo
* Drug: SAR439859
* Drug: Palbociclib
* Drug: Letrozole
* Drug: Goserelin
* Drug: Letrozole-matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Adult participants with loco-regional recurrent or metastatic disease not amenable to curative treatment. Confirmed diagnosis of ER+/HER2- breast cancer. No prior systemic treatment for loco-regional recurrent or metastatic disease. Measurable disease evaluable per Response Evaluation Criterion in Solid Tumors (RECIST) v.1.1 or non-measurable bone-only disease. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Participants should be willing to provide tumor tissue. Capable of giving informed consent. Exclusion criteria: Known active brain metastases. Prior neo (adjuvant) treatment with any selective estrogen receptor degrader (SERD). Inadequate organ and marrow function. Disease recurrence while on, or within 12 months of completion of (neo)adjuvant endocrine therapy. Pregnant, breastfeeding, or woman of childbearing potential unwilling to use recommended contraception methods. Male participants who disagree to follow contraception. Participants with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term. Participants with significant concomitant illness. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Letrozole + Palbociclib<br>Participants received letrozole 2.5 milligrams (mg) capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg orally (PO), once daily (QD) from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks). Goserelin once every 4 weeks in pre/peri menopausal women and men. | Drug: Amcenestrant-matching placebo<br>* Pharmaceutical form: Tablets Route of Administration: Oral<br>Drug: Palbociclib<br>* Pharmaceutical form: Capsules/Tablets Route of Administration: Oral<br>* Other names: Ibrance;Drug: Letrozole<br>* Pharmaceutical form: Capsules Route of Administration: Orally<br>Drug: Goserelin<br>* Pharmaceutical form: Depot Injection Route of Administration: Subcutaneous<br>|
| Experimental: Amcenestrant + Palbociclib<br>Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death, or study cut-off date, whichever comes first (maximum exposure: 109 weeks). Goserelin once every 4 weeks in pre/peri menopausal women and men. | Drug: SAR439859<br>* Pharmaceutical form: Tablets Route of Administration: Oral<br>* Other names: Amcenestrant;Drug: Palbociclib<br>* Pharmaceutical form: Capsules/Tablets Route of Administration: Oral<br>* Other names: Ibrance;Drug: Goserelin<br>* Pharmaceutical form: Depot Injection Route of Administration: Subcutaneous<br>Drug: Letrozole-matching placebo<br>* Pharmaceutical form: Capsules Route of Administration: Orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time interval (in months) from the date of randomization to the date of first documented tumor progression as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) assessed by local radiologist or investigator, or death (due to any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. | From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first (maximum duration: 81 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the interval (in months) from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant was known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. | From randomization to the death due to any cause or data cut-off date, whichever comes first (maximum duration: 81 weeks) | 
| 12-month Progression-free Survival (PFS) Rate | Percentage of participants who were disease progression-free at Month 12 after randomization were reported in this outcome measure. PFS was defined as the time interval (in months) from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by local radiologist or investigator, or death (due to any cause), whichever comes first. PD as per RECIST 1.1: at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. The PFS rate at Month 12 was estimated using the Kaplan-Meier method and provided an estimation of the percentage of participants who were disease progression-free at Month 12 after randomization. | Month 12 | 
| Percentage of Participants With Objective Response | Objective response was defined as percentage of participants having a partial response (PR) or complete response (CR) according to the RECIST version 1.1 assessed by investigator. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30%decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 81 weeks) | 
| Duration of Response (DOR) | DOR was defined as time (in months) from first documented evidence of CR or PR until disease progression determined by investigator as per RECIST 1.1, or start of any anti-cancer therapy, or death from any cause, whichever occurs first. For participants with ongoing response at the time of the analysis, DOR was censored at the date of the last valid disease assessment not showing documented progression performed before the initiation of a new anticancer treatment (if any). As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. | From the date of first response of CR or PR until disease progression or death, or start of any anti-cancer therapy or data cut-off date, whichever comes first (maximum duration: 81 weeks) | 
| Percentage of Participants With Clinical Benefit | Clinical Benefit was defined as the percentage of participants having a confirmed CR, PR, or stable disease (SD) for at least 24 weeks determined by investigator as per RECIST 1.1, from date of randomization until disease progression, or death, or data cut-off date, or initiation of post treatment anti-cancer therapy, whichever occurs first. As per RECIST 1.1; CR was defined as disappearance of all target, non-target lesions & normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference Baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. | From randomization until disease progression, or death, or data cut-off date, whichever comes first (maximum duration: 81 weeks) | 
| Progression-free Survival on Next Line of Therapy (PFS2) | PFS2 was defined as the time interval (in months) from the date of randomization to the date of first documentation of PD on the next systemic anti-cancer therapy according to investigator, or death due to any cause in the absence of documented PD on the next systemic anti-cancer therapy, whichever occurs first. PD was defined as at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. | From randomization to date first documented disease progression on the next systemic anti-cancer therapy, or death due to any cause, or data cut-off date, whichever comes first (maximum duration: 81 weeks) | 
| Pharmacokinetics: Plasma Concentrations of Amcenestrant | Amcenestrant plasma concentrations at specified time points were reported. Data for this outcome measure was not planned to be collected and analyzed for Letrozole+Palbociclib arm as pre-specified in protocol. | Cycle 1 Day 1: 3 hours (hr) post-dose, Cycle 1 Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 3 hr post-dose, Cycle 2 Day 15: pre-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 7 Day 1: pre-dose, Cycle 10 Day 1: pre-dose | 
| Pharmacokinetics: Plasma Concentrations of Palbociclib | Palbociclib plasma concentrations at specified time points were reported. | Cycle 1 Day 1: 3 hr post-dose, Cycle 1 Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 3 hr post-dose, Cycle 2 Day 15: pre-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 7 Day 1: pre-dose, Cycle 10 Day 1: pre-dose | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | EORTC-QLQ-C30: cancer-specific instrument with 30 questions for evaluation of new chemotherapy & assessment of participant reported outcome. These include 5 functional scales, 9 symptom scales, & Global Health Status/quality of life scale (GHS/QoL). All 14 items/domains were scored on scale of 1 (not at all) to 4 (very much) & GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional & GHS/QoL=higher level of functioning, & higher score for symptoms scales=higher symptom burden. Least Square (LS) mean and Standard Error (SE) were derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 21]) for each domain was reported in this outcome measure. | Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks]) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | QLQ-BR23: disease-specific Health-related QOL assesses breast cancer impact & side effects of treatment. EORTCQLQ- BR23 contains 23 items: multi-item scales & single-item measures. 4 functional scales (body image, sexual functioning, sexual enjoyment, future perspective) & 4 scales related to symptoms of disease or treatment (arm symptoms, breast symptoms, systemic therapy side effects, & upset by hair loss). All items scored 1 (not at all) to 4 (very much). Scores of all scales transformed from raw scores to linear scales ranging 0-100. Higher score for functional scales=better outcome; higher score for symptoms scales=higher symptom burden. LS mean & SE were derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value & stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 21]) for each domain was reported. | Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks]) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores | EORTC QLQ-BR45: comprised of all 23 items from the QLQ-BR23 plus an additional 22 items assessing endocrine therapy symptoms (10 items), endocrine sexual symptoms (4 items), breast satisfaction (2 items), and skin mucosis symptoms (6 items). All items scored 1 (not at all) to 4 (very much). Scores of all scales transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional scales = better outcome; higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from Mixed Model Repeated Measures (MMRM) model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 21]) for each domain (endocrine therapy symptoms, endocrine sexual symptoms, breast satisfaction and skin mucosis symptoms) was reported. | Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks]) | 
| Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score | EQ-5D-5L is a standardized measure of health status, provides a simple, generic measure of health for clinical and economic appraisal, and consists of 2 sections: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L VAS. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 21]) for VAS was reported in this outcome measure. | Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks]) | 
| Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value Score | EQ-5D-5L: consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) & VAS. The EQ-5D descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, & extreme problems. Response options are measured with 5-point Likert scale (for 5L version). The EQ-5D-5L responses are converted into single index utility score between 0 to 1, where higher score indicates better health state & lower score indicate worse health state. LS mean and SE were derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values overall treatment (i.e., each cycle [Cycle 1 up to Cycle 21]) for health utility index value score was reported in this outcome measure. | Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks]) | 
| Time to First Chemotherapy | Time to chemotherapy was defined as the time interval (in months) from the date of randomization to the start date of the first chemotherapy after disease progression. | From randomization to the start date of the first chemotherapy (maximum duration: 81 weeks) | 
| Number of Participants With Hematological Abnormalities During the Treatment Period | Hematological parameters assessed were anemia, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, platelet count decreased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 5.0 (NCI-CTCAE v 5.0), where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Treatment period was defined as the time from the first dose of study treatments up to 30 days after last dose of study treatment. | From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks) | 
| Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period | Liver Function parameters assessed were aspartate aminotransferase increased, alanine aminotransferase increased, alkaline phosphatase increased, total bilirubin increased, gamma-glutamyl transferase increased. Parameters were assessed as per the NCI-CTCAE v 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Treatment period was defined as the time from the first dose of study treatments up to 30 days after last dose of study treatment. Participants with Grade 3 and 4 liver function abnormalities were reported in this outcome measure. | From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks) |