Study of Amcenestrant (SAR439859) Versus Tamoxifen for Patients With Hormone Receptor-positive (HR+) Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity

Study Overview
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Brief Summary
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This was a phase III, randomized, double blind, multicenter, 2-arm study evaluating the efficacy and safety of amcenestrant compared with tamoxifen in participants with hormone receptor-positive early breast cancer who discontinued adjuvant aromatase inhibitor (AI) therapy due to treatment related toxicity. The primary objective was to demonstrate the superiority of amcenestrant versus tamoxifen on invasive breast cancer-free survival. The treatment duration per participant was to be 5 years, followed with a subsequent 5-years follow-up period. For the treatment period, visits were scheduled at the start of treatment, then at 4 weeks and 12 weeks after treatment start, and then every 12 weeks for the first 2 years and every 24 weeks for year 3 to 5. For the follow-up period, visits were scheduled 30 days after last treatment and then every 12 months. Three periods were planned: A screening period of up to 28 days, A treatment period of up to 5 years, A follow-up period of up to 5 years.

Detailed Description
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Study duration per participant was to be approximately 10 years.

Official Title
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A Randomized, Multicenter, Double-blind, Phase 3 Study of Amcenestrant (SAR439859) Versus Tamoxifen for the Treatment of Patients With Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative or Positive, Stage IIB-III Breast Cancer Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Amcenestrant
* Drug: Tamoxifen
* Drug: Amcenestrant-matching placebo
* Drug: Tamoxifen-matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants with histologically confirmed diagnosis of adenocarcinoma of the breast with documentation of hormone receptor-positive status, irrespective of human epidermal growth factor receptor 2 (HER2) status NOTE: Participants with HER2-positive breast cancer were eligible only if they had completed their adjuvant anti-HER2 treatment and chemotherapy. With Stage IIB or Stage III (invasive breast cancer) who had undergone breast surgery and adjuvant radiation (if indicated) for the current malignancy. Who had received prior aromatase inhibitors (AIs) (letrozole, anastrozole or exemestane or any sequence thereof) per the following: Adjuvant AI therapy was discontinued due to AI treatment-related toxicity; Minimum of 6 months duration and maximum of 30 months duration (from initiation of first AI if there was a switch between AIs) of AI therapy was required. Absence of locoregional and/or advanced/metastatic disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Capable of giving signed informed consent. Exclusion Criteria: Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of amcenestrant and/or tamoxifen. Participants unable to swallow normally or unable to take tablets and capsules. Predictable poor compliance to oral treatment. Active inflammatory bowel disease or chronic diarrhea, active hepatitis A/B/C, hepatic cirrhosis, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection or banding procedures. History of prior breast cancer treated with AI. Any other solid tumor or lymphoma diagnosis was not allowed except if the participant had been free from disease for equal to greater than (=>5) years. Pregnant or nursing women, or women of child-bearing potential without a negative pregnancy test prior to randomization. Participants with unrecovered acute toxic effects of prior AI therapy or surgical procedures. Uncontrolled intercurrent illness, including psychiatric conditions that would have limited compliance with study requirements. Treatment with any selective estrogen receptor degrader (SERD), tamoxifen or toremifene were not allowed as prior adjuvant therapy but could have been used as neoadjuvant therapy for a total duration of 3 months. Participants who were treated with a SERD, tamoxifen or toremifene in the neoadjuvant setting and who experienced disease progression were not allowed. Prior treatment with raloxifene or tamoxifen for bone health, risk reduction, or a prior breast cancer was allowed provided this was discontinued at least 3 years before diagnosis of current breast cancer. Ongoing treatment with HER2 directed therapy. Appropriate wash out between the last dose of HER2 directed therapy and randomization should have been at least 4 weeks. The above information was not intended to contain all considerations relevant to a 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 |
| --- | --- |
| Experimental: Amcenestrant with tamoxifen-matching placebo arm<br>Amcenestrant dose, once daily, continuously. Tamoxifen-matching placebo, once daily, continuously. | Drug: Amcenestrant<br>* tablet, oral<br>Drug: Tamoxifen-matching placebo<br>* tablet, oral<br>|
| Active Comparator: Tamoxifen with amcenestrant-matching placebo<br>Tamoxifen dose, once daily, continuously. Amcenestrant-matching placebo, once daily, continuously. | Drug: Tamoxifen<br>* tablet, oral<br>Drug: Amcenestrant-matching placebo<br>* tablet, oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Breast Cancer-free Survival (IBCFS) | IBCFS was defined according to standardized definitions for efficacy outcome measure in adjuvant breast cancer trials (STEEP) criteria version 2.0 as the time interval from the date of randomization to the date of the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence (IIBTR): invasive breast cancer involving the same breast parenchyma as the original primary; local-regional invasive breast cancer recurrence: invasive breast cancer in the axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast; distant recurrence: metastatic disease-breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer, invasive contralateral breast cancer; death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. | From randomization to the date of first occurrence of IBCFS event (maximum exposure duration: 155 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-Free Survival (IDFS) | IDFS according to STEEP criteria version 2.0 was defined as the time interval from the date of randomization to the date of the first occurrence of one of the following events: IIBTR: invasive breast cancer involving the same breast parenchyma as the original primary; local-regional invasive breast cancer recurrence: invasive breast cancer in the axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast; distant recurrence: metastatic disease-breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer; invasive contralateral breast cancer; second non-breast primary invasive cancer; death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. | From randomization to the date of first occurrence of IDFS event (maximum exposure duration: 155 days) | 
| Distant Recurrence-free Survival (DRFS) | DRFS according to STEEP criteria version 2.0 was defined as the time interval from the date of randomization to the date of the first occurrence of one of the following events: distant recurrence or death attributable to any cause (including breast cancer, non-breast cancer, or unknown cause). | From randomization to the date of the first occurrence of distant recurrence or death due to any cause, whichever occurs first (maximum exposure duration: 155 days) | 
| Locoregional Recurrences-free Survival (LRRFS) | LRRFS was defined as the time interval from the date of randomization to the date of the first occurrence of one of the following events: local/regional ipsilateral recurrence, invasive contralateral breast cancer or death attributable to any cause (including breast cancer, non-breast cancer, or unknown cause). | From randomization to the date of the first occurrence of local/regional ipsilateral recurrence or breast cancer or death due to any cause, whichever occurs first (maximum exposure duration: 155 days) | 
| Overall Survival (OS) | Overall survival was defined as the time interval from the date of randomization to the date of documented death (due to any cause). | From randomization to the date of death due to any cause (maximum exposure duration: 155 days) | 
| Breast Cancer-specific Survival (BCSS) | BCSS was defined as the time interval from the date of randomization to the date of documented death attributable to breast cancer cause. | From randomization to the date of death due to breast cancer (maximum exposure duration: 155 days) | 
| Change From Baseline in Overall Side Effect Bother As Measured By Functional Assessment of Cancer Therapy Item GP-5 (FACT-GP5) Scale Scores | FACT-GP5 is a single-item from the Functional Assessment of Cancer Therapy-General (FACT-G) scale in which participants report their bother by side effects of treatment response. Responses were given on a 5- point Likert-type scale with score range from 0 (not at all bothered by side effect) to 4 (very much bothered by side effects). Higher scores indicate a higher degree of side effect bother. End of treatment (EOT) visit was 30 days after the last IMP administration. | Baseline, Cycle 3, 4, 5, 6, 7, 10, 13, 16, 19, 22, 25, 28, 34, 40, 46, 52, & 58 and at end of treatment (maximum exposure: any day up to 155 days) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23): Systemic Therapy Side Effects Scale Score | QLQ-BR23: 23-item disease-specific participant reported outcome measure of disease-related symptoms, treatment-related symptoms, and functioning relevant to participants with breast cancer. It consisted of 4 functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and 4 symptoms scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptom). Systemic therapy side effects scale consisted of 7 items & each item was rated on a 4-point scale with responses as: 1= not at all, 2= a little, 3= quite a bit, 4= very much. A linear transformation was applied to raw scores so that all transformed scores are within 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. Negative change from baseline= improvement of side effects, positive change = deterioration. EOT visit was 30 days after last IMP administration. | Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 34, 40, 46, 52, & 58 and at end of treatment (maximum exposure: any day up to 155 days) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30): Global Health Status/Quality of Life (GHQ) Scale Score | EORTC-QLQ-C30: cancer-specific instrument with 30 questions for evaluation of new chemotherapy & assessment of participant reported outcome. EORTC QLQ-C30 included global health status/quality of life (GHS/QOL), functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 were rated on a 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale and were rated on a 7-point scale (1/Very Poor to 7/Excellent). All scales were transformed from raw scores to linear scales ranging 0 to 100. A high score represented a favorable outcome with a best quality of life for participant. EOT visit was 30 days after last IMP administration. | Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 34, 40, 46, 52, & 58 and at end of treatment (maximum exposure: any day up to 155 days) | 
| Plasma Concentration of Amcenestrant |  | Pre-dose on Cycle 2 Day 1, Cycle 7 Day 1, Cycle 13 Day 1 and Cycle 25 Day 1 |