Breast Cancer
Conditions
Brief summary
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
Study duration per participant was to be approximately 10 years.
Interventions
DRUGAmcenestrant
tablet, oral
DRUGTamoxifen
tablet, oral
tablet, oral
DRUGTamoxifen-matching placebo
tablet, oral
Sponsors
Breast International Group
Alliance Foundation Trials, LLC.
European Organisation for Research and Treatment of Cancer - EORTC
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-dummy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Invasive Breast Cancer-free Survival (IBCFS) | From randomization to the date of first occurrence of IBCFS event (maximum exposure duration: 155 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distant Recurrence-free Survival (DRFS) | 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) | 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). |
| Locoregional Recurrences-free Survival (LRRFS) | 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) | 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). |
| Overall Survival (OS) | From randomization to the date of death due to any cause (maximum exposure duration: 155 days) | Overall survival was defined as the time interval from the date of randomization to the date of documented death (due to any cause). |
| Breast Cancer-specific Survival (BCSS) | From randomization to the date of death due to breast cancer (maximum exposure duration: 155 days) | BCSS was defined as the time interval from the date of randomization to the date of documented death attributable to breast cancer cause. |
| Invasive Disease-Free Survival (IDFS) | From randomization to the date of first occurrence of IDFS event (maximum exposure duration: 155 days) | 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. |
| 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 | 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) | 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. |
| 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 | 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) | 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. |
| Plasma Concentration of Amcenestrant | Pre-dose on Cycle 2 Day 1, Cycle 7 Day 1, Cycle 13 Day 1 and Cycle 25 Day 1 | — |
| Change From Baseline in Overall Side Effect Bother As Measured By Functional Assessment of Cancer Therapy Item GP-5 (FACT-GP5) Scale Scores | 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) | 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. |
Countries
Chile, China
Participant flow
Recruitment details
The study was conducted at 2 active centers in Chile and China. A total of 6 participants were screened between 17 February 2022 and 11 August 2022, of which 3 participants were randomized and exposed to study treatment.
Pre-assignment details
Randomization stratified by prior exposure to (neo)adjuvant aromatase inhibitor therapy, (neo)adjuvant chemotherapy & HER2 status, CDK4/6 inhibitor (Yes/No), geographic regions, men' or peri-/pre-menopausal women vs. post-menopausal women. Study was initially planned with two treatment arms (i.e. amcenestrant & tamoxifen), however no participants were exposed to tamoxifen arm due to premature discontinuation & study closure by sponsor thus none of the participants were enrolled in tamoxifen arm.
Participants by arm
| Arm | Count |
|---|---|
| Amcenestrant 200 mg + Tamoxifen-Matching Placebo Participants received amcenestrant 200 mg along with tamoxifen-matching placebo orally PO, QD from Day 1 to Day 28 of each 28-day treatment cycle and were followed-up until diagnosis of disease recurrence per IBCFS definition (recurrence of one of following: IIBTR; local-regional invasive breast cancer recurrence; distant recurrence, invasive contralateral breast cancer, death) or any other withdrawal criterion whichever occurs first (maximum exposure duration: 155 days). | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Sponsor decision to terminate study | 3 |
Baseline characteristics
| Characteristic | Amcenestrant 200 mg + Tamoxifen-Matching Placebo |
|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 2 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
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.
Time frame: From randomization to the date of first occurrence of IBCFS event (maximum exposure duration: 155 days)
Population: No invasive breast cancer event data was collected because of the early termination of the study by the Sponsor and thus IBCFS was not analyzed. Therefore, no data is reported for this outcome measure.
Secondary
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.
Time frame: From randomization to the date of death due to breast cancer (maximum exposure duration: 155 days)
Population: Analysis was performed on randomized population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amcenestrant 200 mg + Tamoxifen-Matching Placebo | Breast Cancer-specific Survival (BCSS) | NA months |
Secondary
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.
Time frame: 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)
Population: Evaluable data was collected for 1 participant only; and was not presented to protect participant confidentiality.
Secondary
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.
Time frame: 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)
Population: Evaluable data was collected for 1 participant only; and was not presented to protect participant confidentiality.
Secondary
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.
Time frame: 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)
Population: Evaluable data was collected for 2 participants only; and thus, was not presented to protect participant confidentiality.
Secondary
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).
Time frame: 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)
Population: No distant recurrence event data was collected because of the early termination of the study by the Sponsor and thus DRFS was not analyzed. Therefore, no data is reported for this outcome measure.
Secondary
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.
Time frame: From randomization to the date of first occurrence of IDFS event (maximum exposure duration: 155 days)
Population: No Invasive disease event data was collected because of the early termination of the study by the Sponsor and thus IDFS was not analyzed. Therefore, no data is reported for this outcome measure.
Secondary
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).
Time frame: 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)
Population: No locoregional recurrences event data was collected because of the early termination of the study by the Sponsor and thus LRRFS was not analyzed. Therefore, no data is reported for this outcome measure.
Secondary
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).
Time frame: From randomization to the date of death due to any cause (maximum exposure duration: 155 days)
Population: Analysis was performed on randomized population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amcenestrant 200 mg + Tamoxifen-Matching Placebo | Overall Survival (OS) | NA months |
Secondary
Plasma Concentration of Amcenestrant
Time frame: Pre-dose on Cycle 2 Day 1, Cycle 7 Day 1, Cycle 13 Day 1 and Cycle 25 Day 1
Population: Data was not collected and analyzed for this outcome measure due to the early termination of the study by the Sponsor.