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

NCT ID: NCT03284957

Last Updated: 2025-11-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 136 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-20
• Study Completion Date: 2024-11-08

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Amcenestrant

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

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).

Group Type: EXPERIMENTAL

Amcenestrant

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

Palbociclib

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

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.

Group Type: EXPERIMENTAL

Amcenestrant

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

Alpelisib

Intervention Type: DRUG

Pharmaceutical form: tablet

Route of administration: oral

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.

Group Type: EXPERIMENTAL

Amcenestrant

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

Everolimus

Intervention Type: DRUG

Pharmaceutical form: tablet

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.

Group Type: EXPERIMENTAL

Amcenestrant

Intervention Type: DRUG

Pharmaceutical form: capsule

Route of administration: oral

Abemaciclib

Intervention Type: DRUG

Pharmaceutical form: tablet

Interventions

Amcenestrant

Pharmaceutical form: capsule

Route of administration: oral

Intervention Type: DRUG

Palbociclib

Pharmaceutical form: capsule

Route of administration: oral

Intervention Type: DRUG

Alpelisib

Pharmaceutical form: tablet

Route of administration: oral

Intervention Type: DRUG

Everolimus

Pharmaceutical form: tablet

Intervention Type: DRUG

Abemaciclib

Pharmaceutical form: tablet

Intervention Type: DRUG

Other Intervention Names

SAR439859; Ibrance®; Piqray®; Verzenio®

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

University of Colorado - Anschutz Medical Campus- Site Number : 8400005

Aurora, Colorado, United States

Massachusetts General Hospital- Site Number : 8400002

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center - New York - York Avenue- Site Number : 8400003

New York, New York, United States

Fred Hutchinson Cancer Center- Site Number : 8400001

Seattle, Washington, United States

Investigational Site Number : 0560001

Leuven, , Belgium

Investigational Site Number : 1240004

Edmonton, Alberta, Canada

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

Prague, , Czechia

Investigational Site Number : 2030003

Prague, , Czechia

Investigational Site Number : 2500002

Bordeaux, , 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

Milan, Milano, Italy

Investigational Site Number : 6160004

Gdynia, Pomeranian Voivodeship, Poland

Investigational Site Number : 6200001

Lisbon, , Portugal

Investigational Site Number : 6200002

Lisbon, , Portugal

Investigational Site Number : 7240007

Madrid, , Spain

Investigational Site Number : 7240001

Madrid, , Spain

Investigational Site Number : 7240002

Madrid, , Spain

Investigational Site Number : 8260002

Cardiff, Cardiff [Caerdydd Gb-crd], United Kingdom

Investigational Site Number : 8260003

Oxford, Oxfordshire, United Kingdom

Countries

United States; Belgium; Canada; Czechia; France; Italy; Poland; Portugal; Spain; United Kingdom

References

Bardia A, Chandarlapaty S, Linden HM, Ulaner GA, Gosselin A, Cartot-Cotton S, Cohen P, Doroumian S, Paux G, Celanovic M, Pelekanou V, Ming JE, Ternes N, Bouaboula M, Lee JS, Bauchet AL, Campone M. AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer. Nat Commun. 2022 Jul 15;13(1):4116. doi: 10.1038/s41467-022-31668-8.

Reference Type: DERIVED

PMID: 35840573 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://sanofi.trialsummaries.com/Study/StudyDetails?id=26150&tenant=MT_SNY_9011

TED14856 Plain Language Results Summary

Other Identifiers

U1111-1189-4896

Identifier Type: REGISTRY

Identifier Source: secondary_id

2024-512997-89

Identifier Type: REGISTRY

Identifier Source: secondary_id

2017-000690-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

TED14856

Identifier Type: -

Identifier Source: org_study_id