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

NCT03284957 | Terminated Phase 1 Results FDA Drug

• 4 other identifiers: TED14856U1111-1189-48962024-512997-892017-000690-36
• Study Type: interventional
• Target: 136
• Locations: 10 countries
• Sites: 25

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

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (3)

• 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.

  Cycle 1 Day 1 to Cycle 1 Day 28 (cycle duration=28 days)

• 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.

  From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 278 weeks

• 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.

  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

Secondary Outcomes (37)

• 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

Study Arms (5)

Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion

EXPERIMENTAL

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

Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion

EXPERIMENTAL

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; Drug: Palbociclib

Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion

EXPERIMENTAL

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; Drug: Alpelisib

Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion

EXPERIMENTAL

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; Drug: Everolimus

Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion

EXPERIMENTAL

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; Drug: Abemaciclib

Interventions

Amcenestrant DRUG

Pharmaceutical form: capsule Route of administration: oral

Also known as: SAR439859

Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion; Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion; Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion; Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion; Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion

Palbociclib DRUG

Pharmaceutical form: capsule Route of administration: oral

Also known as: Ibrance®

Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion

Alpelisib DRUG

Pharmaceutical form: tablet Route of administration: oral

Also known as: Piqray®

Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion

Everolimus DRUG

Pharmaceutical form: tablet

Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion

Abemaciclib DRUG

Pharmaceutical form: tablet

Also known as: Verzenio®

Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Sanofi: lead

Study Sites (25)

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

Aurora, Colorado, 80045, United States

Location

Massachusetts General Hospital- Site Number : 8400002

Boston, Massachusetts, 02114, United States

Location

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

New York, New York, 10065, United States

Location

Fred Hutchinson Cancer Center- Site Number : 8400001

Seattle, Washington, 98109, United States

Location

Investigational Site Number : 0560001

Leuven, 3000, Belgium

Location

Investigational Site Number : 1240004

Edmonton, Alberta, T6G 1Z2, Canada

Location

Investigational Site Number : 1240003

Vancouver, British Columbia, V5Z 1L3, Canada

Location

Investigational Site Number : 1240002

Toronto, Ontario, M4N 3M5, Canada

Location

Investigational Site Number : 2030002

Brno, 656 53, Czechia

Location

Investigational Site Number : 2030001

Prague, 128 08, Czechia

Location

Investigational Site Number : 2030003

Prague, 140 59, Czechia

Location

Investigational Site Number : 2500002

Bordeaux, 33076, France

Location

Investigational Site Number : 2500005

Lille, 59000, France

Location

Investigational Site Number : 2500003

Lyon, 69373, France

Location

Investigational Site Number : 2500001

Saint-Herblain, 44805, France

Location

Investigational Site Number : 2500004

Villejuif, 94805, France

Location

Investigational Site Number : 3800003

Milan, Milano, 20141, Italy

Location

Investigational Site Number : 6160004

Gdynia, Pomeranian Voivodeship, 81-519, Poland

Location

Investigational Site Number : 6200001

Lisbon, 1649-035, Portugal

Location

Investigational Site Number : 6200002

Lisbon, 1998-018, Portugal

Location

Investigational Site Number : 7240007

Madrid, 28034, Spain

Location

Investigational Site Number : 7240001

Madrid, 28041, Spain

Location

Investigational Site Number : 7240002

Madrid, 28050, Spain

Location

Investigational Site Number : 8260002

Cardiff, Cardiff [Caerdydd Gb-crd], CF14 2TL, United Kingdom

Location

Investigational Site Number : 8260003

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 35840573 DERIVED

Related Links

• TED14856 Plain Language Results Summary

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib; Alpelisib; Everolimus; abemaciclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Sponsor decision to prematurely stop the study, it was not linked to any safety concern.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2017
• First Posted: September 15, 2017
• Study Start: September 20, 2017
• Primary Completion: November 8, 2024
• Study Completion: November 8, 2024
• Last Updated: November 24, 2025
• Results First Posted: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

BE (1); CA (3); CZ (3); ES (3); US (4); PT (2); PL (1); IT (1); GB (2); FR (5)