Breast Cancer
Conditions
Brief summary
Primary Objectives: Dose Escalation: * To assess the incidence rate of dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) as well as the recommended dose (RD) of amcenestrant administered as monotherapy and in combination with palbociclib * To assess the incidence rate of DLT and determine the RD of everolimus or abemaciclib in combination with the selected amcenestrant dose for the combination therapy Safety Run-In: \- To confirm the RD of amcenestrant in combination with alpelisib Dose Expansion: * Antitumor activity using objective response rate (ORR) * Overall safety profile of amcenestrant administered in combination with palbociclib, alpelisib, everolimus, and abemaciclib Secondary Objectives: * Overall safety profile of amcenestrant monotherapy and in combination * Pharmacokinetic (PK) profile of amcenestrant administered as monotherapy or in combination and PK profile of palbociclib, alpelisib, everolimus and abemaciclib * Antitumor activity using ORR, the clinical benefit rate (CBR) and progression free survival (PFS) * Time to first tumor response * Residual ER availability with positron emission tomography (PET) scan \[(18)F\] fluoroestradiol (18F-FES) uptake with increasing doses of amcenestrant * Food effect on PK of amcenestrant * Potential induction/inhibition effect of amcenestrant on cytochrome P450 (CYP) 3A using 4b-OH cholesterol
Detailed description
Duration of the study, per participant, will include eligibility period (screening period) of up to 4 weeks (28 days), treatment period (at least 1 cycle \[28 days\] of study treatment), and end of treatment (EOT) visit at least 22 to 30 days (or until the participant receives another anticancer therapy, whichever is earlier) following the last study treatment administration. The expected enrollment period is approximately 60 months.
Interventions
DRUGAmcenestrant
Pharmaceutical form: capsule Route of administration: oral
DRUGPalbociclib
Pharmaceutical form: capsule Route of administration: oral
DRUGAlpelisib
Pharmaceutical form: tablet Route of administration: oral
DRUGEverolimus
Pharmaceutical form: tablet
DRUGAbemaciclib
Pharmaceutical form: tablet
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be postmenopausal women * Histological diagnosis of breast adenocarcinoma * Locally advanced or metastatic disease * Either primary tumor or any metastatic site to be positive for Estrogen Receptors (ER+) and negative for HER2 (HER2-) receptor * Participants must have been previously treated with at least 6 months of endocrine therapy for advanced disease: * Dose Escalation study parts: Arm #3 - Part F and Arm #5 - Part J: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy Arm #4 -H: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy (exemestane not allowed) \- Dose Expansion study parts: Arm #2: - Part D: no more than 2 prior lines of advanced endocrine therapy for advanced disease are allowed Arm #3, - Part G: patients must have received and progressed on the combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first line (1L) treatment for advanced disease Arm #4 - Part I: participants must have received and progressed on the combination of Aromatase Inhibitors (AI) +CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease (exemestane not allowed) Arm#5: - Part K: up to 1 prior line of a single endocrine therapy for advanced disease Note: Additional patients who relapsed while on previous adjuvant endocrine therapy that was initiated ≥24 months ago, or relapsed \< 12 months after completion of adjuvant endocrine therapy are also allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J and K). * Participants previously treated with chemotherapy for advanced disease: no more than 3 prior chemotherapeutic regimens in Arm #1 Part A, and no more than 1 prior chemotherapeutic regimen in Arms #1, #2, #3, #4, and #5 (Parts B, C, D, F, H and J respectively); prior chemotherapy for advanced disease is not allowed in dose expansion of Arms #3, #4, and #5 (Part G, I and K respectively). * Measurable lesion
Exclusion criteria
* Medical history or ongoing gastrointestinal disorders that could affect absorption of oral study drugs (including difficulties with swallowing capsules) * Participants with any other cancer (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or any other cancer from which the participant has been disease free for \>3 years) * Participants with known brain metastases * Treatment with anticancer agents (including investigational drugs) less than 2 weeks before first study treatment starts (less than 4 weeks if the anticancer agents were antibodies) * Prior treatment with another selective ER down-regulator (SERD) * Dose Escalation study parts (Parts F, H and J): SERDs are not allowed except for fulvestrant which will need a washout of at least 6 weeks prior to the first study drug administration * Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD including fulvestrant will not be allowed * Inadequate hematological and biochemical lab tests * Participants with Gilbert disease * Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts * Treatment with strong P450 (CYP) 3A inducers within 2 weeks before first study treatment * Treatment with OATP1B1/B3 sensitive substrates and which cannot be replaced * Arm#2 Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment starts * More than one prior advanced cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy in Arm #1, Arm #2 (Part C), Arm #3 (Parts F and G), and Arm#4 (Part H). * Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: participants with concurrent or history of pneumonitis * Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment therapies that target the PI3K axis (mTOR inhibitors, AKT inhibitors, PI3K inhibitors) * Arm #3 and #4 (Parts F, G, H and I) only: participants with diabetes mellitus type-I or uncontrolled diabetes mellitus type-II: ie, fasting plasma glucose ≥ 140mg/dl (7.7 mmol/l) or HbA1C \> 6.2% * Arm #3 and #4 (Parts F, G, H and I) only: history of severe cutaneous reaction (eg. Stevens-Johnson syndrome \[SJS\], erythema multiforme \[EM\]), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms \[DRESS\]. * Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw * Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g. viral, bacterial, fungal etc.) * Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis, angioedema due to concomitant treatment with ACE inhibitors, impaired wounds * Arm #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia and hyperglycemia in non-diabetic participants * Arm #4 (Parts H and I) only: treatment with strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers and/or P-gp inhibitors within 2 weeks before the first study treatment administration or 5 elimination half-lives, whichever is the longest * Arm #5 (Parts J and K) only: history or current (controlled/not controlled) venous thromboembolism (i.e. deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | Cycle 1 Day 1 to Cycle 1 Day 28 (cycle duration=28 days) | DLTs: any treatment-emergent adverse event(TEAE) related to study treatment per National Cancer Institute Common Terminology Criteria for AE scale version (v) 4.03:Grade(G)≥3 nonhematological toxicity except:G3 nausea/vomiting resolved to G≤1 in 48 hours(h),G3 diarrhea with therapy and lasting\<48h,G3 hyperglycemia resolved to G≤1 in 48h(Part H);G≥3 hematological toxicity except:G3 anemia,G4 neutropenia\<7days(d),G3 neutropenia without fever/infection,G3 thrombocytopenia without bleeding;elevated total serum bilirubin(BL)\>2xupper limit of normal(except Part F),Part F:G3 hyperglycemia not resolved to G≤2 in 7d after antidiabetic treatment,G2 hyperglycemia not resolved to G≤1 in 21d,G2 alanine aminotransferase(ALT) increase in conjunction with total blood BL G≥2 without liver metastases,G≥3 ALT/aspartate aminotransferase increase for\>4d,G3 rash/maculopapular rash not resolved to G≤1 in 7d;treatment related toxicity causing≥7d omission in Cycle 1 or \>2 weeks delay in Cycle 2 in Part C. |
| Part B: Objective Response Rate (ORR) as Determined by Independent Central Review (ICR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks | ORR was determined by dividing the number of participants who achieved confirmed complete response (CR) or partial response (PR) by the number of participants from the analysis population. ORR was assessed by ICR according to response evaluation criteria in solid tumors (RECIST) v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<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. |
| Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration; approximately 232 weeks for Part D and 11 weeks for Part I | AE was any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily had a causal relationship with the treatment. SAE was any untoward medical occurrence that at any dose, resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed or worsened or became serious during the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Clinical Benefit Rate as Determined by Independent Central Review | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks | CBR was determined by dividing the number of participants who achieved confirmed CR, PR as BOR or SD for ≥24 weeks by the number of participants from the analysis population. CBR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively | DOR was defined as the time interval from the date of the first occurrence of confirmed CR or PR to the date of the first documentation of disease progression or death due to disease progression, whichever occurred first. DOR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression. |
| Part B: Duration of Response as Determined by Independent Central Review | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks | DOR was defined as the time interval from the date of the first occurrence of confirmed CR or PR to the date of the first documentation of disease progression or death due to disease progression, whichever occurred first. DOR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression. |
| Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively | PFS was defined as time from the date of the first treatment intake to the date of the first documentation of objective PD according to RECIST v1.1, clinical PD or death due to any cause, whichever occurred first. PFS was assessed by investigators/local radiologists. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression. |
| Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | From Baseline (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228 weeks for Parts A, B, C, D respectively | ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex droplet digital polymerase chain reaction (ddPCR) after extraction of plasma circulating deoxyribonucleic acid (DNA). The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment. |
| Part B: Objective Response Rate as Determined by Independent Central Review According to Estrogen Receptor 1 Mutation at Baseline | Baseline (Day 1) up to maximum exposure of study treatment; approximately 278 weeks | ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex ddPCR after extraction of plasma circulating DNA. The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment. |
| Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | From Baseline (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228 weeks for Parts A, B, C, D respectively | CBR was determined by dividing the number of participants who achieved confirmed CR, PR as BOR or SD for ≥24 weeks by the number of participants from analysis population. CBR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex ddPCR after extraction of plasma circulating DNA. Baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment. |
| Parts B, D, I: Time to First Confirmed Response as Determined by Investigators/Local Radiologists | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively | The time to first confirmed response was defined as the time interval from the date of first administration of the study treatment to the date of the first occurrence of confirmed CR or PR. The time to first confirmed response was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. |
| Part B: Time to First Confirmed Response as Determined by Independent Central Review | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks | The time to first confirmed response was defined as the time interval from the date of first administration of the study treatment to the date of the first occurrence of confirmed CR or PR. The time to first confirmed response was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. |
| Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | Baseline (within 3 days or more prior to Day 1) and between Day 11 and Day 15 of Cycle 1 (cycle duration=28 days) | Inhibition of estrogen receptor (ER) occupancy investigation using 18F-FES-PET imaging was a limited invasive procedure that allowed assessment of ER presence by assessing the binding of radiolabeled estradiol, the ligand of ER (signal extinction). Number of participants with percentage reduction (≥90%, ≥70%, ≥50% and ≥30%) in 18F-FES-PET signal are reported. The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment. |
| Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | Cycle 1 Day 1 (cycle duration=28 days) | Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. Pharmacokinetic (PK) parameters were determined by non-compartmental analysis. LLOQ value for amcenestrant was 5 nanograms per milliliter (ng/mL). |
| Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | Cycle 1 Day 1 (cycle duration=28 days) | Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. |
| Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | Cycle 1 Day 1 (cycle duration=28 days) | Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. |
| Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | Cycle 1 Day 1 (cycle duration=28 days) | Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. tau=12 h for Part A BID dosing and 24 h for other parts. |
| Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days) | Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. |
| Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days) | Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. |
| Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days) | Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. tau=12 h for Part A BID dosing and 24 h for other parts. |
| Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | From first dose of study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration; approximately 94, 282, 144, 96, 59, 130 weeks for Parts A, B, C, F, H, J respectively | AE was any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily had a causal relationship with the treatment. SAE was any untoward medical occurrence that at any dose, resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed or worsened or became serious during the treatment period. |
| Part B: Cumulated Amount of Amcenestrant Excreted in Urine From Time 0 to 24 Hours (Ae0-24) | Day 22 of Cycle 1 (cycle duration=28 days) | Urine samples were collected at the specified timepoints for the measurement of amcenestrant amount excreted in urine. |
| Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | Days 1 and 3 of Cycle 1 (cycle duration=28 days) | The food effect was assessed by comparing the geometric means of AUC0-24 between Cycle 1 Day 1 (fasted condition) and Cycle 1 Day 3 (fed condition) in Part A. |
| Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | Days 1 and 3 of Cycle 1 (cycle duration=28 days) | The food effect was assessed by comparing the geometric means of Cmax between Cycle 1 Day 1 (fasted condition) and Cycle 1 Day 3 (fed condition) in Part A. |
| Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 21 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant for the measurement of palbociclib concentrations. PK parameters were determined by non-compartmental analysis. |
| Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 21 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 21 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Part F: Time to Reach Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Days 3 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis. |
| Part F: Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Days 3 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis. |
| Part F: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Days 3 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis. |
| Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Days 1 and 22 of Cycle 1 (cycle duration=28 days) | Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis. |
| Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Pre-treatment on Day 1 of Cycle 1; post-treatment on Day 22 of Cycle 1, Day 1 and Day 28 (only for Part J) of Cycle 2 (cycle duration=28 days) | Ratios of 4β-hydroxycholesterol concentrations were calculated from plasma samples collected before and after amcenestrant administration. |
| Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1: Pre-dose (0 hour) on Day 8 (Parts A, B, C, D), Day 15 (Parts B, C, D), Day 21 (Parts C and D) and Day 22 (Parts A, B, F, H, I, J) (cycle duration=28 days) | Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. |
| Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively | ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. |
| Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively | CBR was determined by dividing the number of participants who achieved confirmed CR, PR as best overall response (BOR) or stable disease (SD) for ≥24 weeks by the number of participants from the analysis population. CBR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. |
Countries
Belgium, Canada, Czechia, France, Italy, Poland, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 25 sites in 10 countries between 20-Sep-2017 and 08-Nov-2024. A total of 136 participants were enrolled in the study. Sponsor decided to prematurely stop the study, it was not linked to any safety concern.
Pre-assignment details
The study consisted of dose-escalation phases (Parts A, C, H, J), safety run-in phase (Part F) and dose-expansion phases (Parts B, D, G, I, K). Participants received amcenestrant as monotherapy (Parts A, B) or in combination with palbociclib (Parts C, D), alpelisib (Part F), everolimus (Parts H, I) or abemaciclib (Part J). Parts G and K were never initiated due to the early termination of the study. Reason for not completed = reason for permanent full treatment discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Amcenestrant 20 mg Participants received amcenestrant 20 mg capsule orally QD in a fasted state (no dose on Cycle 1 Day 2, dose administered in a fed state on Cycle 1 Day 3 only) in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part A: Amcenestrant 150 mg Participants received amcenestrant 150 mg capsule orally QD in a fasted state (no dose on Cycle 1 Day 2, dose administered in a fed state on Cycle 1 Day 3 only) in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part A: Amcenestrant 200 mg Participants received amcenestrant 200 mg capsule orally QD in a fasted state (no dose on Cycle 1 Day 2, dose administered in a fed state on Cycle 1 Day 3 only) in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 4 |
| Part A: Amcenestrant 400 mg Participants received amcenestrant 400 mg capsule orally QD in a fasted state (no dose on Cycle 1 Day 2, dose administered in a fed state on Cycle 1 Day 3 only) in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part A: Amcenestrant 600 mg Participants received amcenestrant 600 mg capsule orally QD in a fasted state (no dose on Cycle 1 Day 2, dose administered in a fed state on Cycle 1 Day 3 only) in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part A: Amcenestrant 300 mg BID Participants received amcenestrant 300 mg capsule orally once on Cycle 1 Day 1 and then BID from Cycle 1 Day 3 onwards (no dose on Cycle 1 Day 2) in a fed or fasted state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 6 |
| Part B: Amcenestrant 400 mg Participants received amcenestrant 400 mg capsule orally QD in a fed or fasted state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 49 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state along with palbociclib 125 mg capsule orally QD in a fed state for 21 consecutive days followed by 7 days off treatment in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 9 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg Participants received amcenestrant 400 mg capsule orally QD in a fed state along with palbociclib 125 mg capsule orally QD in a fed state for 21 consecutive days followed by 7 days off treatment in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 6 |
| Part D: Amcenestrant 200 mg + Palbociclib 125 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state along with palbociclib 125 mg capsule orally QD in a fed state for 21 consecutive days followed by 7 days off treatment in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 30 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state from Cycle 1 Day 4 onwards along with alpelisib 300 mg tablet orally QD in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 8 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state along with everolimus 5 mg tablet orally QD in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state along with everolimus 10 mg tablet orally QD in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part I: Amcenestrant 200 mg + Everolimus 10 mg Participants received amcenestrant 200 mg capsule orally QD in a fed state along with everolimus 10 mg tablet orally QD in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 1 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID Participants received amcenestrant 200 mg capsule orally QD in a fed state along with abemaciclib 100 mg tablet orally BID in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 3 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID Participants received amcenestrant 200 mg capsule orally QD in a fed state along with abemaciclib 150 mg tablet orally BID in a fed state in 28-day cycles until disease progression, unacceptable toxicity, participant's wish to stop the study, or any other reason, whichever came first. | 2 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 4 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 6 | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Progressive Disease | 3 | 3 | 4 | 3 | 3 | 5 | 45 | 8 | 5 | 18 | 7 | 2 | 3 | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Amcenestrant 20 mg | Part A: Amcenestrant 150 mg | Part A: Amcenestrant 200 mg | Part A: Amcenestrant 400 mg | Part A: Amcenestrant 600 mg | Part A: Amcenestrant 300 mg BID | Part B: Amcenestrant 400 mg | Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Part D: Amcenestrant 200 mg + Palbociclib 125 mg | Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Part H: Amcenestrant 200 mg + Everolimus 5 mg | Part H: Amcenestrant 200 mg + Everolimus 10 mg | Part I: Amcenestrant 200 mg + Everolimus 10 mg | Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Age, Customized From 18 - 64 years | 1 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 5 Participants | 29 Participants | 6 Participants | 2 Participants | 19 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 83 Participants |
| Age, Customized From 65 - 84 years | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 17 Participants | 3 Participants | 4 Participants | 9 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 47 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not reported | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 13 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 32 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 35 Participants | 4 Participants | 4 Participants | 29 Participants | 6 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 98 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 6 Participants | 49 Participants | 9 Participants | 6 Participants | 30 Participants | 8 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 136 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 0 / 4 | 0 / 3 | 1 / 3 | 0 / 6 | 4 / 49 | 1 / 9 | 0 / 6 | 0 / 30 | 2 / 8 | 0 / 3 | 0 / 3 | 0 / 1 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 3 / 3 | 6 / 6 | 49 / 49 | 9 / 9 | 6 / 6 | 29 / 30 | 8 / 8 | 3 / 3 | 3 / 3 | 1 / 1 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 1 / 4 | 0 / 3 | 1 / 3 | 3 / 6 | 15 / 49 | 2 / 9 | 1 / 6 | 8 / 30 | 6 / 8 | 1 / 3 | 0 / 3 | 1 / 1 | 0 / 3 | 1 / 2 |
Outcome results
Primary
Part B: Objective Response Rate (ORR) as Determined by Independent Central Review (ICR)
ORR was determined by dividing the number of participants who achieved confirmed complete response (CR) or partial response (PR) by the number of participants from the analysis population. ORR was assessed by ICR according to response evaluation criteria in solid tumors (RECIST) v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<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.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Objective Response Rate (ORR) as Determined by Independent Central Review (ICR) | 10.9 percentage of participants |
Primary
Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs)
DLTs: any treatment-emergent adverse event(TEAE) related to study treatment per National Cancer Institute Common Terminology Criteria for AE scale version (v) 4.03:Grade(G)≥3 nonhematological toxicity except:G3 nausea/vomiting resolved to G≤1 in 48 hours(h),G3 diarrhea with therapy and lasting\<48h,G3 hyperglycemia resolved to G≤1 in 48h(Part H);G≥3 hematological toxicity except:G3 anemia,G4 neutropenia\<7days(d),G3 neutropenia without fever/infection,G3 thrombocytopenia without bleeding;elevated total serum bilirubin(BL)\>2xupper limit of normal(except Part F),Part F:G3 hyperglycemia not resolved to G≤2 in 7d after antidiabetic treatment,G2 hyperglycemia not resolved to G≤1 in 21d,G2 alanine aminotransferase(ALT) increase in conjunction with total blood BL G≥2 without liver metastases,G≥3 ALT/aspartate aminotransferase increase for\>4d,G3 rash/maculopapular rash not resolved to G≤1 in 7d;treatment related toxicity causing≥7d omission in Cycle 1 or \>2 weeks delay in Cycle 2 in Part C.
Time frame: Cycle 1 Day 1 to Cycle 1 Day 28 (cycle duration=28 days)
Population: The DLT-evaluable population included participants who received 1 cycle (28 days, oral administration), with intake of at least 75% of intended doses, unless they discontinued study treatment before Cycle 1 completion due to a DLT, and in Part A had an evaluable 18F-fluorestradiol (18F-FES) positron emission tomography (PET) scan at baseline and between Days 11 and 15 of first cycle. Any participant who developed a DLT in Part A despite absence of evaluable 18F-FES-PET scan was also included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part A: Amcenestrant 150 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part A: Amcenestrant 200 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part A: Amcenestrant 400 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part A: Amcenestrant 600 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part A: Amcenestrant 300 mg BID | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs) | 0 Participants |
Primary
Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs)
AE was any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily had a causal relationship with the treatment. SAE was any untoward medical occurrence that at any dose, resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed or worsened or became serious during the treatment period.
Time frame: From first dose of study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration; approximately 232 weeks for Part D and 11 weeks for Part I
Population: The safety population included all registered participants exposed to the study treatment, regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 30 Participants |
| Part A: Amcenestrant 20 mg | Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 8 Participants |
| Part A: Amcenestrant 150 mg | Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 1 Participants |
| Part A: Amcenestrant 150 mg | Parts D, I: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 1 Participants |
Secondary
Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction
Inhibition of estrogen receptor (ER) occupancy investigation using 18F-FES-PET imaging was a limited invasive procedure that allowed assessment of ER presence by assessing the binding of radiolabeled estradiol, the ligand of ER (signal extinction). Number of participants with percentage reduction (≥90%, ≥70%, ≥50% and ≥30%) in 18F-FES-PET signal are reported. The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment.
Time frame: Baseline (within 3 days or more prior to Day 1) and between Day 11 and Day 15 of Cycle 1 (cycle duration=28 days)
Population: The safety population included all registered participants exposed to the study treatment, regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 1 Participants |
| Part A: Amcenestrant 20 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 0 Participants |
| Part A: Amcenestrant 20 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 1 Participants |
| Part A: Amcenestrant 20 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 1 Participants |
| Part A: Amcenestrant 150 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 3 Participants |
| Part A: Amcenestrant 150 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 3 Participants |
| Part A: Amcenestrant 150 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 3 Participants |
| Part A: Amcenestrant 150 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 3 Participants |
| Part A: Amcenestrant 200 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 4 Participants |
| Part A: Amcenestrant 200 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 2 Participants |
| Part A: Amcenestrant 200 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 3 Participants |
| Part A: Amcenestrant 200 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 4 Participants |
| Part A: Amcenestrant 400 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 3 Participants |
| Part A: Amcenestrant 400 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 2 Participants |
| Part A: Amcenestrant 400 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 3 Participants |
| Part A: Amcenestrant 400 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 3 Participants |
| Part A: Amcenestrant 600 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 3 Participants |
| Part A: Amcenestrant 600 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 3 Participants |
| Part A: Amcenestrant 600 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 3 Participants |
| Part A: Amcenestrant 600 mg | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 3 Participants |
| Part A: Amcenestrant 300 mg BID | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥30% Reduction | 3 Participants |
| Part A: Amcenestrant 300 mg BID | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥90% Reduction | 2 Participants |
| Part A: Amcenestrant 300 mg BID | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥50% Reduction | 2 Participants |
| Part A: Amcenestrant 300 mg BID | Part A: Number of Participants With 18F-Fluorestradiol Positron Emission Tomography Percentage Reduction | ≥70% Reduction | 2 Participants |
Secondary
Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant
The food effect was assessed by comparing the geometric means of AUC0-24 between Cycle 1 Day 1 (fasted condition) and Cycle 1 Day 3 (fed condition) in Part A.
Time frame: Days 1 and 3 of Cycle 1 (cycle duration=28 days)
Population: The food-effect population included participants who received study treatment in fed condition on Cycle 1 Day 3 and in fasted condition on Cycle 1 Day 1 in Part A. As pre-specified in SAP, food effect was assessed in Part A QD regimen cohorts only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | 1.05 ratio |
| Part A: Amcenestrant 150 mg | Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | 0.69 ratio |
| Part A: Amcenestrant 200 mg | Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | 1.77 ratio |
| Part A: Amcenestrant 400 mg | Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | 1.12 ratio |
| Part A: Amcenestrant 600 mg | Part A (QD Regimen): Geometric Mean Ratio of Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of Amcenestrant | 1.38 ratio |
Secondary
Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant
The food effect was assessed by comparing the geometric means of Cmax between Cycle 1 Day 1 (fasted condition) and Cycle 1 Day 3 (fed condition) in Part A.
Time frame: Days 1 and 3 of Cycle 1 (cycle duration=28 days)
Population: The food-effect population included participants who received study treatment in fed condition on Cycle 1 Day 3 and in fasted condition on Cycle 1 Day 1 in Part A. As pre-specified in SAP, food effect was assessed in Part A QD regimen cohorts only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | 0.80 ratio |
| Part A: Amcenestrant 150 mg | Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | 0.41 ratio |
| Part A: Amcenestrant 200 mg | Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | 1.67 ratio |
| Part A: Amcenestrant 400 mg | Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | 1.38 ratio |
| Part A: Amcenestrant 600 mg | Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant | 1.43 ratio |
Secondary
Part B: Clinical Benefit Rate as Determined by Independent Central Review
CBR was determined by dividing the number of participants who achieved confirmed CR, PR as BOR or SD for ≥24 weeks by the number of participants from the analysis population. CBR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Clinical Benefit Rate as Determined by Independent Central Review | 28.3 percentage of participants |
Secondary
Part B: Cumulated Amount of Amcenestrant Excreted in Urine From Time 0 to 24 Hours (Ae0-24)
Urine samples were collected at the specified timepoints for the measurement of amcenestrant amount excreted in urine.
Time frame: Day 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoint are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Cumulated Amount of Amcenestrant Excreted in Urine From Time 0 to 24 Hours (Ae0-24) | 30800 ng | Standard Deviation 36100 |
Secondary
Part B: Duration of Response as Determined by Independent Central Review
DOR was defined as the time interval from the date of the first occurrence of confirmed CR or PR to the date of the first documentation of disease progression or death due to disease progression, whichever occurred first. DOR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set. Only participants with CR or PR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Duration of Response as Determined by Independent Central Review | NA weeks |
Secondary
Part B: Objective Response Rate as Determined by Independent Central Review According to Estrogen Receptor 1 Mutation at Baseline
ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex ddPCR after extraction of plasma circulating DNA. The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment.
Time frame: Baseline (Day 1) up to maximum exposure of study treatment; approximately 278 weeks
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set. Only participants with data collected for each specified category are reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Objective Response Rate as Determined by Independent Central Review According to Estrogen Receptor 1 Mutation at Baseline | Wild-Type | 15.4 percentage of participants |
| Part A: Amcenestrant 20 mg | Part B: Objective Response Rate as Determined by Independent Central Review According to Estrogen Receptor 1 Mutation at Baseline | Mutated | 5.3 percentage of participants |
| Part A: Amcenestrant 20 mg | Part B: Objective Response Rate as Determined by Independent Central Review According to Estrogen Receptor 1 Mutation at Baseline | Unknown | 0 percentage of participants |
Secondary
Part B: Time to First Confirmed Response as Determined by Independent Central Review
The time to first confirmed response was defined as the time interval from the date of first administration of the study treatment to the date of the first occurrence of confirmed CR or PR. The time to first confirmed response was assessed by ICR according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set. Only participants with CR or PR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Part B: Time to First Confirmed Response as Determined by Independent Central Review | 31.1 weeks |
Secondary
Part F: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant
Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis.
Time frame: Days 3 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part F: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 3 | 28700 ng*h/mL | Standard Deviation 7890 |
| Part A: Amcenestrant 20 mg | Part F: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 22 | 27300 ng*h/mL | Standard Deviation 6910 |
Secondary
Part F: Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant
Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis.
Time frame: Days 3 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part F: Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 3 | 2430 ng/mL | Standard Deviation 631 |
| Part A: Amcenestrant 20 mg | Part F: Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 22 | 3480 ng/mL | Standard Deviation 516 |
Secondary
Part F: Time to Reach Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant
Blood samples were collected after 3-day repeated oral administrations of alpelisib as monotherapy (Day 3) and after 22-day repeated oral administrations of alpelisib in combination with repeated doses of amcenestrant (Day 22). PK parameters were determined by non-compartmental analysis.
Time frame: Days 3 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part F: Time to Reach Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 3 | 3.02 hour |
| Part A: Amcenestrant 20 mg | Part F: Time to Reach Maximum Plasma Concentration of Alpelisib After Repeated Oral Administrations Alone or in Combination With Amcenestrant | Cycle 1 Day 22 | 1.69 hour |
Secondary
Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 994 ng*h/mL | Standard Deviation 700 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 610 ng*h/mL | Standard Deviation 170 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 47.6 ng*h/mL | Standard Deviation 0.468 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 314 ng*h/mL | Standard Deviation 141 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 1 | 295 ng*h/mL | Standard Deviation 9.12 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 22 | 997 ng*h/mL | Standard Deviation 219 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 22 | 1050 ng*h/mL | Standard Deviation 532 |
| Part A: Amcenestrant 20 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 160 ng*h/mL | Standard Deviation 45 |
| Part A: Amcenestrant 150 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 1330 ng*h/mL | Standard Deviation 478 |
| Part A: Amcenestrant 150 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 1130 ng*h/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 926 ng*h/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 554 ng*h/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 218 ng*h/mL | — |
Secondary
Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 91.6 ng/mL | Standard Deviation 58.4 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 22 | 109 ng/mL | Standard Deviation 45.6 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 17.8 ng/mL | Standard Deviation 3.46 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 69.1 ng/mL | Standard Deviation 20.5 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 6.37 ng/mL | Standard Deviation 0.514 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 35.1 ng/mL | Standard Deviation 17.2 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 1 | 31.2 ng/mL | Standard Deviation 2.84 |
| Part A: Amcenestrant 20 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 22 | 100 ng/mL | Standard Deviation 17.3 |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 22 | 153 ng/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 152 ng/mL | Standard Deviation 44.5 |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 22.0 ng/mL | Standard Deviation 4.24 |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 22 | 87.8 ng/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 1 | 65.5 ng/mL | Standard Deviation 8.13 |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 55.3 ng/mL | Standard Deviation 22 |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 89.5 ng/mL | — |
| Part A: Amcenestrant 150 mg | Part J: Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 106 ng/mL | — |
Secondary
Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of abemaciclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 2.67 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 22 | 3.00 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 4.00 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 5.75 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 2.67 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 3.88 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 1 | 8.07 hour |
| Part A: Amcenestrant 20 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 22 | 1.03 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 22 | 8.67 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 1 | 6.00 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Abemaciclib: Cycle 1 Day 22 | 8.00 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 1 | 6.50 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M2: Cycle 1 Day 22 | 4.00 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 1 | 8.00 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M18: Cycle 1 Day 22 | 4.00 hour |
| Part A: Amcenestrant 150 mg | Part J: Time to Reach Maximum Plasma Concentration of Abemaciclib and Its Metabolites M2, M18 and M20 After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | M20: Cycle 1 Day 1 | 8.50 hour |
Secondary
Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline
CBR was determined by dividing the number of participants who achieved confirmed CR, PR as BOR or SD for ≥24 weeks by the number of participants from analysis population. CBR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex ddPCR after extraction of plasma circulating DNA. Baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment.
Time frame: From Baseline (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228 weeks for Parts A, B, C, D respectively
Population: Analysis was performed on the efficacy population. As pre-specified in SAP, analysis was performed on pooled population \[Part A and B: Amcenestrant (Dose \>20 mg); Parts C and D: Amcenestrant 200 mg + Palbociclib 125 mg\] based on the pharmacodynamic effect to maximize sample size within each arm to provide more robust estimates. Only participants with data collected for each specified category are reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | Wild-Type | 36.7 percentage of participants |
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | Mutated | 32.1 percentage of participants |
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | Unknown | 0 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | Wild-Type | 70.4 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D: Clinical Benefit Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 Mutation at Baseline | Mutated | 63.6 percentage of participants |
Secondary
Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations
Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. tau=12 h for Part A BID dosing and 24 h for other parts.
Time frame: Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 1630 ng*h/mL | Standard Deviation 1120 |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 15900 ng*h/mL | Standard Deviation 7350 |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 13900 ng*h/mL | Standard Deviation 4380 |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 36800 ng*h/mL | Standard Deviation 23500 |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 42700 ng*h/mL | Standard Deviation 11200 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 36500 ng*h/mL | Standard Deviation 7680 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 43200 ng*h/mL | Standard Deviation 16200 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 20600 ng*h/mL | Standard Deviation 7520 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 33100 ng*h/mL | Standard Deviation 11400 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 17600 ng*h/mL | Standard Deviation 7540 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 30600 ng*h/mL | Standard Deviation 11900 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 28300 ng*h/mL | Standard Deviation 21100 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 25000 ng*h/mL | Standard Deviation 7180 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 8270 ng*h/mL | — |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 26600 ng*h/mL | Standard Deviation 12900 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval of Amcenestrant After Repeated Oral Administrations | 30300 ng*h/mL | — |
Secondary
Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists
CBR was determined by dividing the number of participants who achieved confirmed CR, PR as best overall response (BOR) or stable disease (SD) for ≥24 weeks by the number of participants from the analysis population. CBR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 66.7 percentage of participants |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 75.0 percentage of participants |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 66.7 percentage of participants |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 33.3 percentage of participants |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 25.0 percentage of participants |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 26.1 percentage of participants |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 44.4 percentage of participants |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 50.0 percentage of participants |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 75.9 percentage of participants |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 14.3 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 50 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 33.3 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 66.7 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Clinical Benefit Rate (CBR) as Determined by Investigators/Local Radiologists | 50 percentage of participants |
Secondary
Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists
DOR was defined as the time interval from the date of the first occurrence of confirmed CR or PR to the date of the first documentation of disease progression or death due to disease progression, whichever occurred first. DOR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set. Only participants with CR or PR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | 23.9 weeks |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | NA weeks |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | 32.2 weeks |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | 52.4 weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Duration of Response (DOR) as Determined by Investigators/Local Radiologists | 11.43 weeks |
Secondary
Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations
Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis.
Time frame: Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 218 ng/mL | Standard Deviation 95.3 |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2390 ng/mL | Standard Deviation 1200 |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2150 ng/mL | Standard Deviation 873 |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4020 ng/mL | Standard Deviation 2460 |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 5570 ng/mL | Standard Deviation 962 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 5200 ng/mL | Standard Deviation 296 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4380 ng/mL | Standard Deviation 1230 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2060 ng/mL | Standard Deviation 831 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4350 ng/mL | Standard Deviation 3190 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2120 ng/mL | Standard Deviation 691 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4230 ng/mL | Standard Deviation 1250 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3300 ng/mL | Standard Deviation 1390 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2760 ng/mL | Standard Deviation 411 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 848 ng/mL | — |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3350 ng/mL | Standard Deviation 1230 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3820 ng/mL | — |
Secondary
Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists
ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 33.3 percentage of participants |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 8.7 percentage of participants |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 22.2 percentage of participants |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 34.5 percentage of participants |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 0 percentage of participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Objective Response Rate as Determined by Investigators/Local Radiologists | 50 percentage of participants |
Secondary
Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant
Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations.
Time frame: Cycle 1: Pre-dose (0 hour) on Day 8 (Parts A, B, C, D), Day 15 (Parts B, C, D), Day 21 (Parts C and D) and Day 22 (Parts A, B, F, H, I, J) (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 0 ng/mL | — |
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 6.80 ng/mL | Standard Deviation 9.62 |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 75.1 ng/mL | — |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 91.4 ng/mL | — |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 159 ng/mL | Standard Deviation 35.8 |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 76.1 ng/mL | Standard Deviation 56 |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 871 ng/mL | — |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 388 ng/mL | Standard Deviation 327 |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 302 ng/mL | — |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 348 ng/mL | Standard Deviation 197 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 1510 ng/mL | Standard Deviation 1030 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 2220 ng/mL | Standard Deviation 1100 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 15 | 553 ng/mL | Standard Deviation 605 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 665 ng/mL | Standard Deviation 581 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 598 ng/mL | Standard Deviation 460 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 15 | 328 ng/mL | Standard Deviation 168 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 348 ng/mL | Standard Deviation 180 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 21 | 359 ng/mL | Standard Deviation 132 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 21 | 297 ng/mL | Standard Deviation 144 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 389 ng/mL | Standard Deviation 234 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 15 | 243 ng/mL | Standard Deviation 151 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 21 | 223 ng/mL | Standard Deviation 187 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 15 | 226 ng/mL | Standard Deviation 198 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 8 | 303 ng/mL | Standard Deviation 294 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 410 ng/mL | Standard Deviation 449 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 326 ng/mL | Standard Deviation 216 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 346 ng/mL | Standard Deviation 128 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 114 ng/mL | — |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 214 ng/mL | Standard Deviation 138 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Plasma Concentration Observed Before Treatment Administration (Ctrough) of Amcenestrant | Cycle 1 Day 22 | 229 ng/mL | — |
Secondary
Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists
PFS was defined as time from the date of the first treatment intake to the date of the first documentation of objective PD according to RECIST v1.1, clinical PD or death due to any cause, whichever occurred first. PFS was assessed by investigators/local radiologists. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5 mm in the sum. Appearance of 1 or more new lesions was also considered progression.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 7.3 weeks |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 31.3 weeks |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 31.3 weeks |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 32.3 weeks |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 7.9 weeks |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 7.7 weeks |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 8.3 weeks |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 44.3 weeks |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 60.0 weeks |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | 79.7 weeks |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Progression-Free Survival (PFS) as Determined by Investigators/Local Radiologists | NA weeks |
Secondary
Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations
Blood samples were collected at the specified timepoints for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis.
Time frame: Parts A, B, F, H, I, J: Cycle 1 Day 22; Parts C and D: Cycle 1 Day 21 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.17 hour |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.97 hour |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.07 hour |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.95 hour |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3.00 hour |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.98 hour |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3.00 hour |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4.88 hour |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4.00 hour |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4.00 hour |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3.22 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.47 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4.17 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 4.07 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 2.67 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, F, H, I, J: Time to Reach Maximum Plasma Concentration of Amcenestrant After Repeated Oral Administrations | 3.33 hour |
Secondary
Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration
Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis. tau=12 h for Part A BID dosing and 24 h for other parts.
Time frame: Cycle 1 Day 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoint are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 1040 ng*h/mL | Standard Deviation 560 |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 9140 ng*h/mL | Standard Deviation 8730 |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 13600 ng*h/mL | Standard Deviation 13800 |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 40400 ng*h/mL | Standard Deviation 17500 |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 61100 ng*h/mL | Standard Deviation 36300 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 28200 ng*h/mL | Standard Deviation 16900 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 50900 ng*h/mL | Standard Deviation 26000 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 21300 ng*h/mL | Standard Deviation 5910 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 46400 ng*h/mL | Standard Deviation 4400 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 21400 ng*h/mL | Standard Deviation 10000 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 14100 ng*h/mL | Standard Deviation 3190 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 20900 ng*h/mL | Standard Deviation 4330 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 17900 ng*h/mL | — |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 36500 ng*h/mL | Standard Deviation 25100 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Dosing Interval (AUC0-tau) of Amcenestrant After a Single Oral Administration | 38000 ng*h/mL | Standard Deviation 13800 |
Secondary
Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration
Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis.
Time frame: Cycle 1 Day 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoint are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 187 ng/mL | Standard Deviation 46.7 |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 1310 ng/mL | Standard Deviation 1380 |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 1650 ng/mL | Standard Deviation 1340 |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 4740 ng/mL | Standard Deviation 2920 |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 7010 ng/mL | Standard Deviation 4180 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 4620 ng/mL | Standard Deviation 2740 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 6020 ng/mL | Standard Deviation 2810 |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 2270 ng/mL | Standard Deviation 1130 |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 5470 ng/mL | Standard Deviation 1280 |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 2500 ng/mL | Standard Deviation 1110 |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 1700 ng/mL | Standard Deviation 355 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 1940 ng/mL | Standard Deviation 664 |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 2330 ng/mL | — |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 4500 ng/mL | Standard Deviation 2860 |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Maximum Plasma Concentration (Cmax) of Amcenestrant After a Single Oral Administration | 5360 ng/mL | Standard Deviation 750 |
Secondary
Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration
Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. Pharmacokinetic (PK) parameters were determined by non-compartmental analysis. LLOQ value for amcenestrant was 5 nanograms per milliliter (ng/mL).
Time frame: Cycle 1 Day 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoint are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.470 hour |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Time Interval Between Administration and the Sampling Preceding the First Concentration Above the Lower Limit of Quantification (LLOQ) (Tlag) of Amcenestrant After a Single Oral Administration | 0.00 hour |
Secondary
Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration
Blood samples were collected at the specified timepoint for the measurement of amcenestrant concentrations. PK parameters were determined by non-compartmental analysis.
Time frame: Cycle 1 Day 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoint are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 1.52 hour |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.00 hour |
| Part A: Amcenestrant 200 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 2.98 hour |
| Part A: Amcenestrant 400 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.00 hour |
| Part A: Amcenestrant 600 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.03 hour |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 2.98 hour |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.98 hour |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 5.82 hour |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 4.97 hour |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.03 hour |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 4.02 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.98 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 4.00 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.88 hour |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, D, H, I, J: Time to Reach Maximum Plasma Concentration (Tmax) of Amcenestrant After a Single Oral Administration | 3.50 hour |
Secondary
Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline
ORR was determined by dividing the number of participants who achieved confirmed CR or PR by the number of participants from the analysis population. ORR was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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. The ESR1 gene mutation status (mutated or wild-type) was analyzed by multiplex droplet digital polymerase chain reaction (ddPCR) after extraction of plasma circulating deoxyribonucleic acid (DNA). The baseline value was defined as the last value or measurement taken up to the date and time of the first dose of study treatment irrespective of the treatment.
Time frame: From Baseline (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228 weeks for Parts A, B, C, D respectively
Population: Analysis was performed on the efficacy population. As pre-specified in statistical analysis plan (SAP), analysis was performed on pooled population \[Part A and B: Amcenestrant (Dose \>20 mg); Parts C and D: Amcenestrant 200 mg + Palbociclib 125 mg\] based on the pharmacodynamic effect to maximize sample size within each arm to provide more robust estimates. Only participants with data collected for each specified category are reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | Wild-Type | 13.3 percentage of participants |
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | Mutated | 3.6 percentage of participants |
| Part A: Amcenestrant 20 mg | Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | Unknown | 0 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | Wild-Type | 33.3 percentage of participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, D: Objective Response Rate as Determined by Investigators/Local Radiologists According to Estrogen Receptor 1 (ESR1) Mutation at Baseline | Mutated | 27.3 percentage of participants |
Secondary
Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events
AE was any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily had a causal relationship with the treatment. SAE was any untoward medical occurrence that at any dose, resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed or worsened or became serious during the treatment period.
Time frame: From first dose of study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration; approximately 94, 282, 144, 96, 59, 130 weeks for Parts A, B, C, F, H, J respectively
Population: The safety population included all registered participants exposed to the study treatment, regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part A: Amcenestrant 20 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 0 Participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part A: Amcenestrant 150 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part A: Amcenestrant 200 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 4 Participants |
| Part A: Amcenestrant 200 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part A: Amcenestrant 400 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part A: Amcenestrant 400 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 0 Participants |
| Part A: Amcenestrant 600 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part A: Amcenestrant 600 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 3 Participants |
| Part A: Amcenestrant 300 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 6 Participants |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 15 Participants |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 49 Participants |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 2 Participants |
| Part C: Amcenestrant 400 mg + Palbociclib 125 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 9 Participants |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 6 Participants |
| Part F: Amcenestrant 200 mg + Alpelisib 300 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 8 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 5 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 6 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part H: Amcenestrant 200 mg + Everolimus 10 mg | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 100 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 0 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 0 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 3 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TESAEs | 1 Participants |
| Part J: Amcenestrant 200 mg + Abemaciclib 150 mg BID | Parts A, B, C, F, H, J: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events | TEAEs | 2 Participants |
Secondary
Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol
Ratios of 4β-hydroxycholesterol concentrations were calculated from plasma samples collected before and after amcenestrant administration.
Time frame: Pre-treatment on Day 1 of Cycle 1; post-treatment on Day 22 of Cycle 1, Day 1 and Day 28 (only for Part J) of Cycle 2 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported. The study was terminated prior to data collection for Part J for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 0.817 ratio | Standard Deviation 0.168 |
| Part A: Amcenestrant 20 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 1.09 ratio | Standard Deviation 0.304 |
| Part A: Amcenestrant 150 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 1.18 ratio | Standard Deviation 0.294 |
| Part A: Amcenestrant 150 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 1.13 ratio | Standard Deviation 0.432 |
| Part A: Amcenestrant 200 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 1.29 ratio | Standard Deviation 0.263 |
| Part A: Amcenestrant 200 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 1.39 ratio | Standard Deviation 0.207 |
| Part A: Amcenestrant 400 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 1.61 ratio | Standard Deviation 0.336 |
| Part A: Amcenestrant 400 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 1.83 ratio | Standard Deviation 0.569 |
| Part A: Amcenestrant 600 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 2.24 ratio | Standard Deviation 1.29 |
| Part A: Amcenestrant 600 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 2.40 ratio | Standard Deviation 0.559 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 2.17 ratio | Standard Deviation 0.377 |
| Part A: Amcenestrant 300 mg BID | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 2.99 ratio | Standard Deviation 1.58 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 1 Day 22/Cycle 1 Day 1 | 1.68 ratio | Standard Deviation 0.577 |
| Part C: Amcenestrant 200 mg + Palbociclib 125 mg | Parts A, B, J: Post/Pre--Treatment Ratio of 4 Beta (β)-Hydroxycholesterol | Cycle 2 Day 1/Cycle 1 Day 1 | 1.89 ratio | Standard Deviation 0.627 |
Secondary
Parts B, D, I: Time to First Confirmed Response as Determined by Investigators/Local Radiologists
The time to first confirmed response was defined as the time interval from the date of first administration of the study treatment to the date of the first occurrence of confirmed CR or PR. The time to first confirmed response was assessed by investigators/local radiologists according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 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.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 90, 278, 140, 228, 92, 55, 7, 126 weeks for Parts A, B, C, D, F, H, I, J respectively
Population: The efficacy population included all treated participants with measurable disease at study entry who provided a baseline and at least 1 post-baseline evaluable tumor assessment. Participants with an early progression as per RECIST v1.1 or who died from disease progression were also included in this set. Only participants with CR or PR (responders) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Amcenestrant 20 mg | Parts B, D, I: Time to First Confirmed Response as Determined by Investigators/Local Radiologists | 8.1 weeks |
| Part A: Amcenestrant 150 mg | Parts B, D, I: Time to First Confirmed Response as Determined by Investigators/Local Radiologists | 16.2 weeks |
Secondary
Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 21 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 1040 ng*h/mL | Standard Deviation 257 |
| Part A: Amcenestrant 20 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 1660 ng*h/mL | Standard Deviation 751 |
| Part A: Amcenestrant 150 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 889 ng*h/mL | Standard Deviation 376 |
| Part A: Amcenestrant 150 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 823 ng*h/mL | Standard Deviation 266 |
| Part A: Amcenestrant 200 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 949 ng*h/mL | Standard Deviation 265 |
| Part A: Amcenestrant 200 mg | Parts C and D: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 1570 ng*h/mL | Standard Deviation 523 |
Secondary
Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 21 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 70.4 ng/mL | Standard Deviation 26.1 |
| Part A: Amcenestrant 20 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 98.1 ng/mL | Standard Deviation 37.6 |
| Part A: Amcenestrant 150 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 64.7 ng/mL | Standard Deviation 28.4 |
| Part A: Amcenestrant 150 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 59.4 ng/mL | Standard Deviation 28.1 |
| Part A: Amcenestrant 200 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 62.3 ng/mL | Standard Deviation 17.5 |
| Part A: Amcenestrant 200 mg | Parts C and D: Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 96.3 ng/mL | Standard Deviation 34.9 |
Secondary
Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 21) of palbociclib in combination with amcenestrant for the measurement of palbociclib concentrations. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 21 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 5.70 hour |
| Part A: Amcenestrant 20 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 4.10 hour |
| Part A: Amcenestrant 150 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 3.99 hour |
| Part A: Amcenestrant 150 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 6.00 hour |
| Part A: Amcenestrant 200 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 6.00 hour |
| Part A: Amcenestrant 200 mg | Parts C and D: Time to Reach Maximum Plasma Concentration of Palbociclib After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 21 | 4.75 hour |
Secondary
Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 144 ng*h/mL | Standard Deviation 35 |
| Part A: Amcenestrant 20 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 210 ng*h/mL | Standard Deviation 117 |
| Part A: Amcenestrant 150 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 381 ng*h/mL | Standard Deviation 159 |
| Part A: Amcenestrant 150 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 319 ng*h/mL | Standard Deviation 156 |
| Part A: Amcenestrant 200 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 246 ng*h/mL | — |
| Part A: Amcenestrant 200 mg | Parts H and I: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 295 ng*h/mL | — |
Secondary
Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 38.7 ng/mL | Standard Deviation 21.9 |
| Part A: Amcenestrant 20 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 24.4 ng/mL | Standard Deviation 6.32 |
| Part A: Amcenestrant 150 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 64.8 ng/mL | Standard Deviation 3.54 |
| Part A: Amcenestrant 150 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 37.6 ng/mL | Standard Deviation 15.5 |
| Part A: Amcenestrant 200 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 43.5 ng/mL | — |
| Part A: Amcenestrant 200 mg | Parts H and I: Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 46.7 ng/mL | — |
Secondary
Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant
Blood samples were collected after single dose (Day 1) and repeated oral administrations (Day 22) of everolimus in combination with amcenestrant. PK parameters were determined by non-compartmental analysis.
Time frame: Days 1 and 22 of Cycle 1 (cycle duration=28 days)
Population: The PK population included all participants from the safety population with at least 1 evaluable treatment concentration after study treatment administration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Amcenestrant 20 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 1.02 hour |
| Part A: Amcenestrant 20 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 1.00 hour |
| Part A: Amcenestrant 150 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 2.00 hour |
| Part A: Amcenestrant 150 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 2.08 hour |
| Part A: Amcenestrant 200 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 1 | 1.00 hour |
| Part A: Amcenestrant 200 mg | Parts H and I: Time to Reach Maximum Plasma Concentration of Everolimus After First Dose and Repeated Oral Administrations in Combination With Amcenestrant | Cycle 1 Day 22 | 1.10 hour |