Phase 1/2 Study of Amcenestrant (SAR439859) Single Agent and in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor Positive Advanced Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT03284957
- Lead Sponsor
- Sanofi
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Female
- Target Recruitment
- 136
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion Amcenestrant 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. Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion Everolimus 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. Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion Amcenestrant 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). Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion Amcenestrant 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. Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion Amcenestrant 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. Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion Amcenestrant 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. Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion Palbociclib 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). Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion Alpelisib 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. Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion Abemaciclib 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.
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicities (DLTs) Cycle 1, Day 28 for each treated participant (each cycle is 28 days) Incidence of study treatment-related DLTs at Cycle 1 (Arm #1 Part A, Arm #2 Part C, Arm #3 Part D, Arm #4 Part H, and Arm #5 Part J)
Objective Response Rate (ORR) Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant Proportion of participants with confirmed CR or PR according to RECIST 1.1 assessed by independent central reviewer relative to the total number of treated participants (Arm #1 Part B)
Adverse Events Up to 30 days after last dose of amcenestrant Number of participants with adverse events according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 grade scaling; incidence of adverse events, including laboratory test results and electrocardiogram (ECG) findings that were adverse events (Arm #2 Part D, Arm #3 Part G, Arm #4 Part I, Arm #5 Part K)
- Secondary Outcome Measures
Name Time Method Adverse Events Up to 30 days after last dose of amcenestrant Number of participants with adverse events according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 grade scaling; incidence of adverse events, including laboratory test results and electrocardiogram (ECG) findings that were adverse events in all treatment arms
Duration of response Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant Time from initial response to the first documented tumor progression in all treatment arms
tlag of amcenestrant after single dose Cycle 1, Day 1 and Day 3 (each cycle is 28 days) tlag is interval between administration time and the sampling time preceding the first concentration above the lower limit of quantification of amcenestrant (Arms #1, #2, #4, and #5)
Cmax of amcenestrant after single dose Cycle 1, Day 1 and Day 3 (each cycle is 28 days) Cmax is maximum concentration observed (Arms #1, #2, #4, and #5)
tmax of amcenestrant after repeated dose administration Cycle 1, Day 21 or 22 (each cycle is 28 days) tmax is time to reach Cmax in all treatment arms
Cmax of amcenestrant after repeated dose administration Cycle 1, Day 21 or 22 (each cycle is 28 days) Cmax is maximum concentration observed in all treatment arms
ORR Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant Proportion of participants with complete response (CR) or partial response (PR) according to RECIST 1.1 assessed by investigator/local radiologist relative to the total number of treated participants in all treatment arms
Time to First Response (TTR) Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant Time from the start of treatment to the first objective tumor response observed for participants who achieved CR or PR in all treatment arms
Clinical Benefit Rate (CBR) Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant Proportion of participants with CR or PR or SD ≥24 weeks according to RECIST v.1.1 relative to the total number of treated participants by investigators/local radiologists in all treatment arms and by independent central reviewer in Arm #1 Part B
tmax of amcenestrant after single dose Cycle 1, Day 1 and Day 3 (each cycle is 28 days) tmax is time to reach Cmax (Arms #1, #2, #4, and #5)
AUC0-24 of amcenestrant after single dose Cycle 1, Day 1 and Day 3 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arms #1, #2, #4, and #5)
AUC0-24 of amcenestrant after repeated dose administration Cycle 1, Day 21 or 22 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) in all treatment arms
Ctrough of amcenestrant during repeated dose administration Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1 (each cycle is 28 days) Ctrough is plasma concentration observed just before treatment administration during repeated dosing in all treatment arms
tmax of palbociclib after single dose Cycle 1, Day 1 (each cycle is 28 days) tmax is time to reach Cmax (Arm #2)
Cmax of palbociclib after single dose Cycle 1, Day 1 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #2)
AUC0-24 of palbociclib after single dose Cycle 1, Day 1 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)
tmax of palbociclib after repeated dose administration Cycle 1, Day 21 (each cycle is 28 days) tmax is time to reach Cmax (Arm #2)
Cmax of palbociclib after repeated dose administration Cycle 1, Day 21 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #2)
AUC0-24 of palbociclib after repeated dose administration Cycle 1, Day 21 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)
Urine excretion of amcenestrant Cycle 1, Day 21 (each cycle is 28 days) Urine excretion of amcenestrant during the monotherapy expansion phase (Arm #1 Part B)
Cholesterol concentration ratios Up to Cycle 2 (each cycle is 28 days) Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1)
ER occupancy at 18F-FES-PET imaging Baseline and one assessment in Cycle 1 on Day 11 to 15 (each cycle is 28 days) Inhibition of ER occupancy at 18F-FES-PET imaging (signal extinction) (Arm #1 Part A)
Progression free survival Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant Time interval from the date of the first IMP intake to the date of the first tumor progression assessed by investigators/local radiologists in all treatment arms and (also by IRC in Part B) per RECIST 1.1, or death (due to any cause), whichever comes first.
Observation of tumor changes by FES PET and FDG PET scans Baseline and approximately at Day 15 of Cycle 1 in Part A (each cycle is 28 days) To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET (Arm #1 Part A)
tmax of alpelisib after third dose Cycle 1, Day 3 (each cycle is 28 days) tmax is time to reach Cmax (Arm #3)
Cmax of alpelisib after third dose Cycle 1, Day 3 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #3)
AUC0-24 of alpelisib after third dose Cycle 1, Day 3 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)
tmax of alpelisib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) tmax is time to reach Cmax (Arm #3)
Cmax of alpelisib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #3)
AUC0-24 of alpelisib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)
tmax of everolimus after single dose Cycle 1, Day 1 (each cycle is 28 days) tmax is time to reach Cmax (Arm #4)
Cmax of everolimus after single dose Cycle 1, Day 1 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #4)
AUC0-24 of everolimus after single dose Cycle 1, Day 1 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)
tmax of everolimus after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) tmax is time to reach Cmax (Arm #4)
tmax of abemaciclib after single dose Cycle 1, Day 1 (each cycle is 28 days) tmax is time to reach Cmax (Arm #5)
Cmax of everolimus after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #4)
AUC0-24 of everolimus after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)
Cmax of abemaciclib after single dose Cycle 1, Day 1 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #5)
tmax of abemaciclib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) tmax is time to reach Cmax (Arm #5)
Cmax of abemaciclib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) Cmax is maximum concentration observed (Arm #5)
AUC0-24 of abemaciclib after single dose Cycle 1, Day 1 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)
AUC0-24 of abemaciclib after repeated dose administration Cycle 1, Day 22 (each cycle is 28 days) AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)
Trial Locations
- Locations (25)
Investigational Site Number : 1240003
🇨🇦Vancouver, British Columbia, Canada
Investigational Site Number : 1240002
🇨🇦Toronto, Ontario, Canada
Investigational Site Number : 2030002
🇨🇿Brno, Czechia
Investigational Site Number : 2030001
🇨🇿Praha 2, Czechia
Investigational Site Number : 2030003
🇨🇿Praha 4, Czechia
Investigational Site Number : 2500002
🇫🇷Bordeaux Cedex, France
Investigational Site Number : 2500005
🇫🇷Lille, France
Investigational Site Number : 2500003
🇫🇷Lyon, France
Investigational Site Number : 2500001
🇫🇷Saint-Herblain, France
Investigational Site Number : 2500004
🇫🇷Villejuif, France
Investigational Site Number : 3800003
🇮🇹Milano, Italy
Investigational Site Number : 6160004
🇵🇱Gdynia, Pomorskie, Poland
Investigational Site Number : 6200001
🇵🇹Lisboa, Portugal
Investigational Site Number : 6200002
🇵🇹Lisboa, Portugal
Investigational Site Number : 7240007
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number : 7240002
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number : 7240001
🇪🇸Madrid, Spain
Investigational Site Number : 8260003
🇬🇧Oxford, Oxfordshire, United Kingdom
Investigational Site Number : 8260002
🇬🇧Cardiff, Vale Of Glamorgan, The, United Kingdom
University of Colorado- Site Number : 8400005
🇺🇸Denver, Colorado, United States
Memorial Sloan Kettering Cancer Center- Site Number : 8400003
🇺🇸New York, New York, United States
Seattle Cancer Care Alliance- Site Number : 8400001
🇺🇸Seattle, Washington, United States
Massachusetts General Hospital Site Number : 8400002
🇺🇸Boston, Massachusetts, United States
Investigational Site Number : 0560001
🇧🇪Leuven, Belgium
Investigational Site Number : 1240004
🇨🇦Edmonton, Alberta, Canada