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 (AMEERA-1)

  • End date
    Aug 14, 2024
  • participants needed
  • sponsor
Updated on 26 July 2022
measurable disease
endocrine therapy
hormone therapy
advanced breast cancer
primary tumor
aromatase inhibitor
estrogen receptor
breast adenocarcinoma


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


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.

Condition Breast Cancer
Treatment Everolimus, Midazolam, Palbociclib, Abemaciclib, Alpelisib, SAR439859, Amcenestrant
Clinical Study IdentifierNCT03284957
Last Modified on26 July 2022


Yes No Not Sure

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
Measurable lesion
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)

Exclusion Criteria

Participants with known brain metastases
Inadequate hematological and biochemical lab tests
Participants with Gilbert disease
Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw
Medical history or ongoing gastrointestinal disorders that could affect absorption of
oral study drugs (including difficulties with swallowing capsules)
The above information is not intended to contain all considerations relevant to a patient's
Participants with any other cancer (except for adequately treated basal cell or
potential participation in a clinical trial
squamous cell skin cancer, in situ cervical cancer or any other cancer from which the
participant has been disease free for >3 years)
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
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
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 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 #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)
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