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

Breast Cancer Clinical Trial

— AMEERA-1  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03284957
• Other study ID #: TED14856
• Secondary ID: U1111-1189-48962
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: September 20, 2017
• Est. completion date: December 29, 2027

Study information

• Verified date: February 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 136
• Est. completion date: December 29, 2027
• Est. primary completion date: December 29, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Amcenestrant
Pharmaceutical form: capsule Route of administration: oral
• Palbociclib
Pharmaceutical form: capsule Route of administration: oral
• Alpelisib
Pharmaceutical form: tablet Route of administration: oral
• Everolimus
Pharmaceutical form: tablet
• Abemaciclib
Pharmaceutical form: tablet

Locations

Country	Name	City	State
Belgium	Investigational Site Number : 0560001	Leuven
Canada	Investigational Site Number : 1240004	Edmonton	Alberta
Canada	Investigational Site Number : 1240002	Toronto	Ontario
Canada	Investigational Site Number : 1240003	Vancouver	British Columbia
Czechia	Investigational Site Number : 2030002	Brno
Czechia	Investigational Site Number : 2030001	Praha 2
Czechia	Investigational Site Number : 2030003	Praha 4
France	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
Italy	Investigational Site Number : 3800003	Milano
Poland	Investigational Site Number : 6160004	Gdynia	Pomorskie
Portugal	Investigational Site Number : 6200001	Lisboa
Portugal	Investigational Site Number : 6200002	Lisboa
Spain	Investigational Site Number : 7240001	Madrid
Spain	Investigational Site Number : 7240002	Madrid	Madrid, Comunidad De
Spain	Investigational Site Number : 7240007	Madrid	Madrid, Comunidad De
United Kingdom	Investigational Site Number : 8260002	Cardiff	Vale Of Glamorgan, The
United Kingdom	Investigational Site Number : 8260003	Oxford	Oxfordshire
United States	Massachusetts General Hospital Site Number : 8400002	Boston	Massachusetts
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	tmax of palbociclib after single dose	tmax is time to reach Cmax (Arm #2)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	Cmax of palbociclib after single dose	Cmax is maximum concentration observed (Arm #2)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of palbociclib after repeated dose administration	tmax is time to reach Cmax (Arm #2)	Cycle 1, Day 21 (each cycle is 28 days)
Secondary	Cmax of palbociclib after repeated dose administration	Cmax is maximum concentration observed (Arm #2)	Cycle 1, Day 21 (each cycle is 28 days)
Secondary	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)
Secondary	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)
Secondary	Cholesterol concentration ratios	Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1)	Up to Cycle 2 (each cycle is 28 days)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	tmax of alpelisib after third dose	tmax is time to reach Cmax (Arm #3)	Cycle 1, Day 3 (each cycle is 28 days)
Secondary	Cmax of alpelisib after third dose	Cmax is maximum concentration observed (Arm #3)	Cycle 1, Day 3 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of alpelisib after repeated dose administration	tmax is time to reach Cmax (Arm #3)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	Cmax of alpelisib after repeated dose administration	Cmax is maximum concentration observed (Arm #3)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of everolimus after single dose	tmax is time to reach Cmax (Arm #4)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	Cmax of everolimus after single dose	Cmax is maximum concentration observed (Arm #4)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of everolimus after repeated dose administration	tmax is time to reach Cmax (Arm #4)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	Cmax of everolimus after repeated dose administration	Cmax is maximum concentration observed (Arm #4)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of abemaciclib after single dose	tmax is time to reach Cmax (Arm #5)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	Cmax of abemaciclib after single dose	Cmax is maximum concentration observed (Arm #5)	Cycle 1, Day 1 (each cycle is 28 days)
Secondary	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)
Secondary	tmax of abemaciclib after repeated dose administration	tmax is time to reach Cmax (Arm #5)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	Cmax of abemaciclib after repeated dose administration	Cmax is maximum concentration observed (Arm #5)	Cycle 1, Day 22 (each cycle is 28 days)
Secondary	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)