A Phase 1/2 Study for the Safety, Efficacy, Pharmacokinetic and Pharmacodynamics Evaluation of Amcenestrant (SAR439859), Administered Orally as Monotherapy, Then in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor-positive Advanced Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Sanofi
- 入组人数
- 136
- 试验地点
- 25
- 主要终点
- Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion
Part A: Amcenestrant will be administered orally once daily (QD). Treatment will begin with an identified starting dose. Administration of higher doses to subsequent participants is based on occurrence of DLTs and evaluation of target saturation and PK parameters at initial and subsequent doses, until maximum administered dose (MAD) is reached. Drug will be administered in a 28-day cycle.
Part B: When the dose escalation phase ends, the recommended dose will be administered for the expansion cohort. Drug will be administered in a 28-day cycle.
干预措施: Amcenestrant (Drug)
Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion
Part C: Amcenestrant will be administered in combination with palbociclib: amcenestrant starting oral daily dose will be one dose level below monotherapy RD and palbociclib will be dosed at fixed standard dose. Administration of higher dose of amcenestrant (with standard palbociclib dose) to subsequent participants will be based on occurrence of DLTs at initial and subsequent doses, until MAD of amcenestrant is reached. Drugs will be administered in a 28-day cycle (palbociclib will be administered for 21 days of cycle).
Part D: Based on the results in Part C, participants will be administered either: 1) a determined amcenestrant dose (RD) with standard dose of palbociclib in combination therapy, or 2) one of two randomized dose levels of amcenestrant with standard dose of palbociclib in combination therapy. Drugs will be administered in a 28-day cycle (palbociclib will be administered for 21 days of cycle).
干预措施: Amcenestrant (Drug)
Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion
Part C: Amcenestrant will be administered in combination with palbociclib: amcenestrant starting oral daily dose will be one dose level below monotherapy RD and palbociclib will be dosed at fixed standard dose. Administration of higher dose of amcenestrant (with standard palbociclib dose) to subsequent participants will be based on occurrence of DLTs at initial and subsequent doses, until MAD of amcenestrant is reached. Drugs will be administered in a 28-day cycle (palbociclib will be administered for 21 days of cycle).
Part D: Based on the results in Part C, participants will be administered either: 1) a determined amcenestrant dose (RD) with standard dose of palbociclib in combination therapy, or 2) one of two randomized dose levels of amcenestrant with standard dose of palbociclib in combination therapy. Drugs will be administered in a 28-day cycle (palbociclib will be administered for 21 days of cycle).
干预措施: Palbociclib (Drug)
Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion
Part F: Amcenestrant will be administered in combination with alpelisib at a fixed standard dose. Additional dose levels of amcenestrant with alpelisib could be explored if needed based on the safety and PK results. Lower dose of alpelisib could be explored based on the PK results and safety profile from the initial combination administration. Both amcenestrant and alpelisib will be administered in a 28-day cycle.
Part G: Based on the conclusion in Part F, participants will be administered the determined RD of amcenestrant and alpelisib given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Amcenestrant (Drug)
Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion
Part F: Amcenestrant will be administered in combination with alpelisib at a fixed standard dose. Additional dose levels of amcenestrant with alpelisib could be explored if needed based on the safety and PK results. Lower dose of alpelisib could be explored based on the PK results and safety profile from the initial combination administration. Both amcenestrant and alpelisib will be administered in a 28-day cycle.
Part G: Based on the conclusion in Part F, participants will be administered the determined RD of amcenestrant and alpelisib given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Alpelisib (Drug)
Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion
Part H: Amcenestrant will be administered at the determined RD in combination with 2 dose levels of everolimus. Additional dose levels of amcenestrant with everolimus could be explored if needed based on the safety and PK results. Both amcenestrant and everolimus will be administered in a 28-day cycle.
Part I: Based on the conclusion in Part H, participants will be administered the determined RD of amcenestrant and RD of everolimus given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Amcenestrant (Drug)
Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion
Part H: Amcenestrant will be administered at the determined RD in combination with 2 dose levels of everolimus. Additional dose levels of amcenestrant with everolimus could be explored if needed based on the safety and PK results. Both amcenestrant and everolimus will be administered in a 28-day cycle.
Part I: Based on the conclusion in Part H, participants will be administered the determined RD of amcenestrant and RD of everolimus given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Everolimus (Drug)
Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion
Part J: Amcenestrant will be administered at the determined RD in combination with 2 dose levels of abemaciclib. Additional dose levels of amcenestrant with abemaciclib could be explored if needed based on the safety and PK results. Both amcenestrant and abemaciclib will be administered in a 28-day cycle.
Part K: Based on the conclusion in Part J, participants will be administered the determined RD of amcenestrant and RD of abemaciclib given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Amcenestrant (Drug)
Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion
Part J: Amcenestrant will be administered at the determined RD in combination with 2 dose levels of abemaciclib. Additional dose levels of amcenestrant with abemaciclib could be explored if needed based on the safety and PK results. Both amcenestrant and abemaciclib will be administered in a 28-day cycle.
Part K: Based on the conclusion in Part J, participants will be administered the determined RD of amcenestrant and RD of abemaciclib given in the combination in an expansion cohort. Both study drugs will be administered in a 28-day cycle.
干预措施: Abemaciclib (Drug)
结局指标
主要结局
Parts A, C, F, H, J: Number of Participants With Study Treatment-Related Dose-Limiting Toxicities (DLTs)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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))
- 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))
- 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)
- 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)
- 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))
- Part A (QD Regimen): Geometric Mean Ratio of Maximum Plasma Concentration of Amcenestrant(Days 1 and 3 of Cycle 1 (cycle duration=28 days))
- 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))
- 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)
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))