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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Amcenestrant
* Drug: Palbociclib
* Drug: Alpelisib
* Drug: Everolimus
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion<br>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. | Drug: Amcenestrant<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SAR439859;|
| Experimental: Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion<br>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). | Drug: Amcenestrant<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SAR439859;Drug: Palbociclib<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: Ibrance®;|
| Experimental: Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion<br>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. | Drug: Amcenestrant<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SAR439859;Drug: Alpelisib<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Piqray®;|
| Experimental: Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion<br>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. | Drug: Amcenestrant<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SAR439859;Drug: Everolimus<br>* Pharmaceutical form: tablet<br>|
| Experimental: Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion<br>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. | Drug: Amcenestrant<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SAR439859;Drug: Abemaciclib<br>* Pharmaceutical form: tablet<br>* Other names: Verzenio®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) | 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) | Cycle 1, Day 28 for each treated participant (each cycle is 28 days) | 
| Objective Response Rate (ORR) | 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) | Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant | 
| Adverse Events | 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) | Up to 30 days after last dose of amcenestrant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | 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 | Up to 30 days after last dose of amcenestrant | 
| ORR | 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 | Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Time to First Response (TTR) | Time from the start of treatment to the first objective tumor response observed for participants who achieved CR or PR in all treatment arms | Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Clinical Benefit Rate (CBR) | 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 | Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Duration of response | Time from initial response to the first documented tumor progression in all treatment arms | Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| tlag of amcenestrant after single dose | 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) | Cycle 1, Day 1 and Day 3 (each cycle is 28 days) | 
| tmax of amcenestrant after single dose | tmax is time to reach Cmax (Arms #1, #2, #4, and #5) | Cycle 1, Day 1 and Day 3 (each cycle is 28 days) | 
| Cmax of amcenestrant after single dose | Cmax is maximum concentration observed (Arms #1, #2, #4, and #5) | Cycle 1, Day 1 and Day 3 (each cycle is 28 days) | 
| AUC0-24 of amcenestrant after single dose | 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) | Cycle 1, Day 1 and Day 3 (each cycle is 28 days) | 
| tmax of amcenestrant after repeated dose administration | tmax is time to reach Cmax in all treatment arms | Cycle 1, Day 21 or 22 (each cycle is 28 days) | 
| Cmax of amcenestrant after repeated dose administration | Cmax is maximum concentration observed in all treatment arms | Cycle 1, Day 21 or 22 (each cycle is 28 days) | 
| AUC0-24 of amcenestrant after repeated dose administration | 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 | Cycle 1, Day 21 or 22 (each cycle is 28 days) | 
| Ctrough of amcenestrant during repeated dose administration | Ctrough is plasma concentration observed just before treatment administration during repeated dosing in all treatment arms | Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1 (each cycle is 28 days) | 
| tmax of palbociclib after single dose | tmax is time to reach Cmax (Arm #2) | Cycle 1, Day 1 (each cycle is 28 days) | 
| Cmax of palbociclib after single dose | Cmax is maximum concentration observed (Arm #2) | Cycle 1, Day 1 (each cycle is 28 days) | 
| AUC0-24 of palbociclib after single dose | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2) | Cycle 1, Day 1 (each cycle is 28 days) | 
| tmax of palbociclib after repeated dose administration | tmax is time to reach Cmax (Arm #2) | Cycle 1, Day 21 (each cycle is 28 days) | 
| Cmax of palbociclib after repeated dose administration | Cmax is maximum concentration observed (Arm #2) | Cycle 1, Day 21 (each cycle is 28 days) | 
| AUC0-24 of palbociclib after repeated dose administration | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2) | Cycle 1, Day 21 (each cycle is 28 days) | 
| Urine excretion of amcenestrant | Urine excretion of amcenestrant during the monotherapy expansion phase (Arm #1 Part B) | Cycle 1, Day 21 (each cycle is 28 days) | 
| Cholesterol concentration ratios | Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1) | Up to Cycle 2 (each cycle is 28 days) | 
| ER occupancy at 18F-FES-PET imaging | Inhibition of ER occupancy at 18F-FES-PET imaging (signal extinction) (Arm #1 Part A) | Baseline and one assessment in Cycle 1 on Day 11 to 15 (each cycle is 28 days) | 
| Progression free survival | 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. | Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Observation of tumor changes by FES PET and FDG PET scans | To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET (Arm #1 Part A) | Baseline and approximately at Day 15 of Cycle 1 in Part A (each cycle is 28 days) | 
| tmax of alpelisib after third dose | tmax is time to reach Cmax (Arm #3) | Cycle 1, Day 3 (each cycle is 28 days) | 
| Cmax of alpelisib after third dose | Cmax is maximum concentration observed (Arm #3) | Cycle 1, Day 3 (each cycle is 28 days) | 
| AUC0-24 of alpelisib after third dose | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3) | Cycle 1, Day 3 (each cycle is 28 days) | 
| tmax of alpelisib after repeated dose administration | tmax is time to reach Cmax (Arm #3) | Cycle 1, Day 22 (each cycle is 28 days) | 
| Cmax of alpelisib after repeated dose administration | Cmax is maximum concentration observed (Arm #3) | Cycle 1, Day 22 (each cycle is 28 days) | 
| AUC0-24 of alpelisib after repeated dose administration | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3) | Cycle 1, Day 22 (each cycle is 28 days) | 
| tmax of everolimus after single dose | tmax is time to reach Cmax (Arm #4) | Cycle 1, Day 1 (each cycle is 28 days) | 
| Cmax of everolimus after single dose | Cmax is maximum concentration observed (Arm #4) | Cycle 1, Day 1 (each cycle is 28 days) | 
| AUC0-24 of everolimus after single dose | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4) | Cycle 1, Day 1 (each cycle is 28 days) | 
| tmax of everolimus after repeated dose administration | tmax is time to reach Cmax (Arm #4) | Cycle 1, Day 22 (each cycle is 28 days) | 
| Cmax of everolimus after repeated dose administration | Cmax is maximum concentration observed (Arm #4) | Cycle 1, Day 22 (each cycle is 28 days) | 
| AUC0-24 of everolimus after repeated dose administration | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4) | Cycle 1, Day 22 (each cycle is 28 days) | 
| tmax of abemaciclib after single dose | tmax is time to reach Cmax (Arm #5) | Cycle 1, Day 1 (each cycle is 28 days) | 
| Cmax of abemaciclib after single dose | Cmax is maximum concentration observed (Arm #5) | Cycle 1, Day 1 (each cycle is 28 days) | 
| AUC0-24 of abemaciclib after single dose | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5) | Cycle 1, Day 1 (each cycle is 28 days) | 
| tmax of abemaciclib after repeated dose administration | tmax is time to reach Cmax (Arm #5) | Cycle 1, Day 22 (each cycle is 28 days) | 
| Cmax of abemaciclib after repeated dose administration | Cmax is maximum concentration observed (Arm #5) | Cycle 1, Day 22 (each cycle is 28 days) | 
| AUC0-24 of abemaciclib after repeated dose administration | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5) | Cycle 1, Day 22 (each cycle is 28 days) |