<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03284957</url>
  </required_header>
  <id_info>
    <org_study_id>TED14856</org_study_id>
    <secondary_id>2017-000690-36</secondary_id>
    <secondary_id>U1111-1189-4896</secondary_id>
    <nct_id>NCT03284957</nct_id>
  </id_info>
  <brief_title>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</brief_title>
  <acronym>AMEERA-1</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sanofi</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Objectives:&#xD;
&#xD;
      Dose Escalation:&#xD;
&#xD;
        -  To assess the incidence rate of dose-limiting toxicity (DLT) and to determine the&#xD;
           maximum tolerated dose (MTD) as well as the recommended dose (RD) of amcenestrant&#xD;
           administered as monotherapy and in combination with palbociclib&#xD;
&#xD;
        -  To assess the incidence rate of DLT and determine the RD of everolimus or abemaciclib in&#xD;
           combination with the selected amcenestrant dose for the combination therapy&#xD;
&#xD;
      Safety Run-In:&#xD;
&#xD;
      - To confirm the RD of amcenestrant in combination with alpelisib&#xD;
&#xD;
      Dose Expansion:&#xD;
&#xD;
        -  Antitumor activity using objective response rate (ORR)&#xD;
&#xD;
        -  Overall safety profile of amcenestrant administered in combination with palbociclib,&#xD;
           alpelisib, everolimus, and abemaciclib&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  Overall safety profile of amcenestrant monotherapy and in combination&#xD;
&#xD;
        -  Pharmacokinetic (PK) profile of amcenestrant administered as monotherapy or in&#xD;
           combination and PK profile of palbociclib, alpelisib, everolimus and abemaciclib&#xD;
&#xD;
        -  Antitumor activity using ORR, the clinical benefit rate (CBR) and progression free&#xD;
           survival (PFS)&#xD;
&#xD;
        -  Time to first tumor response&#xD;
&#xD;
        -  Residual ER availability with positron emission tomography (PET) scan [(18)F]&#xD;
           fluoroestradiol (18F-FES) uptake with increasing doses of amcenestrant&#xD;
&#xD;
        -  Food effect on PK of amcenestrant&#xD;
&#xD;
        -  Potential induction/inhibition effect of amcenestrant on cytochrome P450 (CYP) 3A using&#xD;
           4b-OH cholesterol&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Duration of the study, per participant, will include eligibility period (screening period) of&#xD;
      up to 4 weeks (28 days), treatment period (at least 1 cycle [28 days] of study treatment),&#xD;
      and end of treatment (EOT) visit at least 22 to 30 days (or until the participant receives&#xD;
      another anticancer therapy, whichever is earlier) following the last study treatment&#xD;
      administration. The expected enrollment period is approximately 60 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 20, 2017</start_date>
  <completion_date type="Anticipated">December 29, 2027</completion_date>
  <primary_completion_date type="Anticipated">December 29, 2027</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose Limiting Toxicities (DLTs)</measure>
    <time_frame>Cycle 1, Day 28 for each treated participant (each cycle is 28 days)</time_frame>
    <description>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)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant</time_frame>
    <description>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)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Up to 30 days after last dose of amcenestrant</time_frame>
    <description>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)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Up to 30 days after last dose of amcenestrant</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ORR</measure>
    <time_frame>Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to First Response (TTR)</measure>
    <time_frame>Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant</time_frame>
    <description>Time from the start of treatment to the first objective tumor response observed for participants who achieved CR or PR in all treatment arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR)</measure>
    <time_frame>Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant</time_frame>
    <description>Time from initial response to the first documented tumor progression in all treatment arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tlag of amcenestrant after single dose</measure>
    <time_frame>Cycle 1, Day 1 and Day 3 (each cycle is 28 days)</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of amcenestrant after single dose</measure>
    <time_frame>Cycle 1, Day 1 and Day 3 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arms #1, #2, #4, and #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of amcenestrant after single dose</measure>
    <time_frame>Cycle 1, Day 1 and Day 3 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arms #1, #2, #4, and #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of amcenestrant after single dose</measure>
    <time_frame>Cycle 1, Day 1 and Day 3 (each cycle is 28 days)</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of amcenestrant after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 or 22 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax in all treatment arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of amcenestrant after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 or 22 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed in all treatment arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of amcenestrant after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 or 22 (each cycle is 28 days)</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ctrough of amcenestrant during repeated dose administration</measure>
    <time_frame>Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1 (each cycle is 28 days)</time_frame>
    <description>Ctrough is plasma concentration observed just before treatment administration during repeated dosing in all treatment arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of palbociclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of palbociclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of palbociclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of palbociclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of palbociclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of palbociclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 21 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine excretion of amcenestrant</measure>
    <time_frame>Cycle 1, Day 21 (each cycle is 28 days)</time_frame>
    <description>Urine excretion of amcenestrant during the monotherapy expansion phase (Arm #1 Part B)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cholesterol concentration ratios</measure>
    <time_frame>Up to Cycle 2 (each cycle is 28 days)</time_frame>
    <description>Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ER occupancy at 18F-FES-PET imaging</measure>
    <time_frame>Baseline and one assessment in Cycle 1 on Day 11 to 15 (each cycle is 28 days)</time_frame>
    <description>Inhibition of ER occupancy at 18F-FES-PET imaging (signal extinction) (Arm #1 Part A)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Observation of tumor changes by FES PET and FDG PET scans</measure>
    <time_frame>Baseline and approximately at Day 15 of Cycle 1 in Part A (each cycle is 28 days)</time_frame>
    <description>To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET (Arm #1 Part A)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of alpelisib after third dose</measure>
    <time_frame>Cycle 1, Day 3 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of alpelisib after third dose</measure>
    <time_frame>Cycle 1, Day 3 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of alpelisib after third dose</measure>
    <time_frame>Cycle 1, Day 3 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of alpelisib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of alpelisib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of alpelisib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of everolimus after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of everolimus after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of everolimus after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of everolimus after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of everolimus after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of everolimus after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of abemaciclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of abemaciclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of abemaciclib after single dose</measure>
    <time_frame>Cycle 1, Day 1 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax of abemaciclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>tmax is time to reach Cmax (Arm #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of abemaciclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>Cmax is maximum concentration observed (Arm #5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-24 of abemaciclib after repeated dose administration</measure>
    <time_frame>Cycle 1, Day 22 (each cycle is 28 days)</time_frame>
    <description>AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">136</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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).&#xD;
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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amcenestrant</intervention_name>
    <description>Pharmaceutical form: capsule&#xD;
Route of administration: oral</description>
    <arm_group_label>Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion</arm_group_label>
    <arm_group_label>Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion</arm_group_label>
    <arm_group_label>Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion</arm_group_label>
    <arm_group_label>Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion</arm_group_label>
    <arm_group_label>Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion</arm_group_label>
    <other_name>SAR439859</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palbociclib</intervention_name>
    <description>Pharmaceutical form: capsule&#xD;
Route of administration: oral</description>
    <arm_group_label>Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion</arm_group_label>
    <other_name>Ibrance®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alpelisib</intervention_name>
    <description>Pharmaceutical form: tablet&#xD;
Route of administration: oral</description>
    <arm_group_label>Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion</arm_group_label>
    <other_name>Piqray®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Pharmaceutical form: tablet</description>
    <arm_group_label>Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Abemaciclib</intervention_name>
    <description>Pharmaceutical form: tablet</description>
    <arm_group_label>Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion</arm_group_label>
    <other_name>Verzenio®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Participants must be postmenopausal women&#xD;
&#xD;
          -  Histological diagnosis of breast adenocarcinoma&#xD;
&#xD;
          -  Locally advanced or metastatic disease&#xD;
&#xD;
          -  Either primary tumor or any metastatic site to be positive for Estrogen Receptors&#xD;
             (ER+) and negative for HER2 (HER2-) receptor&#xD;
&#xD;
          -  Participants must have been previously treated with at least 6 months of endocrine&#xD;
             therapy for advanced disease:&#xD;
&#xD;
          -  Dose Escalation study parts:&#xD;
&#xD;
        Arm #3 - Part F and Arm #5 - Part J: up to 2 prior lines of either single endocrine therapy&#xD;
        and/or endocrine-based therapy Arm #4 -H: up to 2 prior lines of either single endocrine&#xD;
        therapy and/or endocrine-based therapy (exemestane not allowed)&#xD;
&#xD;
        - Dose Expansion study parts: Arm #2: - Part D: no more than 2 prior lines of advanced&#xD;
        endocrine therapy for advanced disease are allowed Arm #3, - Part G: patients must have&#xD;
        received and progressed on the combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor&#xD;
        as the first line (1L) treatment for advanced disease Arm #4 - Part I: participants must&#xD;
        have received and progressed on the combination of Aromatase Inhibitors (AI) +CDK4/6&#xD;
        Inhibitor as the first line (1L) treatment for advanced disease (exemestane not allowed)&#xD;
        Arm#5: - Part K: up to 1 prior line of a single endocrine therapy for advanced disease&#xD;
        Note: Additional patients who relapsed while on previous adjuvant endocrine therapy that&#xD;
        was initiated ≥24 months ago, or relapsed &lt; 12 months after completion of adjuvant&#xD;
        endocrine therapy are also allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J&#xD;
        and K).&#xD;
&#xD;
          -  Participants previously treated with chemotherapy for advanced disease: no more than 3&#xD;
             prior chemotherapeutic regimens in Arm #1 Part A, and no more than 1 prior&#xD;
             chemotherapeutic regimen in Arms #1, #2, #3, #4, and #5 (Parts B, C, D, F, H and J&#xD;
             respectively); prior chemotherapy for advanced disease is not allowed in dose&#xD;
             expansion of Arms #3, #4, and #5 (Part G, I and K respectively).&#xD;
&#xD;
          -  Measurable lesion&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Medical history or ongoing gastrointestinal disorders that could affect absorption of&#xD;
             oral study drugs (including difficulties with swallowing capsules)&#xD;
&#xD;
          -  Participants with any other cancer (except for adequately treated basal cell or&#xD;
             squamous cell skin cancer, in situ cervical cancer or any other cancer from which the&#xD;
             participant has been disease free for &gt;3 years)&#xD;
&#xD;
          -  Participants with known brain metastases&#xD;
&#xD;
          -  Treatment with anticancer agents (including investigational drugs) less than 2 weeks&#xD;
             before first study treatment starts (less than 4 weeks if the anticancer agents were&#xD;
             antibodies)&#xD;
&#xD;
          -  Prior treatment with another selective ER down-regulator (SERD)&#xD;
&#xD;
          -  Dose Escalation study parts (Parts F, H and J): SERDs are not allowed except for&#xD;
             fulvestrant which will need a washout of at least 6 weeks prior to the first study&#xD;
             drug administration&#xD;
&#xD;
          -  Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD&#xD;
             including fulvestrant will not be allowed&#xD;
&#xD;
          -  Inadequate hematological and biochemical lab tests&#xD;
&#xD;
          -  Participants with Gilbert disease&#xD;
&#xD;
          -  Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks&#xD;
             before study treatment starts&#xD;
&#xD;
          -  Treatment with strong P450 (CYP) 3A inducers within 2 weeks before first study&#xD;
             treatment&#xD;
&#xD;
          -  Treatment with OATP1B1/B3 sensitive substrates and which cannot be replaced&#xD;
&#xD;
          -  Arm#2 Treatment with strong CYP3A inhibitors within 2 weeks before first study&#xD;
             treatment starts&#xD;
&#xD;
          -  More than one prior advanced cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy&#xD;
             in Arm #1, Arm #2 (Part C), Arm #3 (Parts F and G), and Arm#4 (Part H).&#xD;
&#xD;
          -  Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: participants with&#xD;
             concurrent or history of pneumonitis&#xD;
&#xD;
          -  Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment therapies that&#xD;
             target the PI3K axis (mTOR inhibitors, AKT inhibitors, PI3K inhibitors)&#xD;
&#xD;
          -  Arm #3 and #4 (Parts F, G, H and I) only: participants with diabetes mellitus type-I&#xD;
             or uncontrolled diabetes mellitus type-II: ie, fasting plasma glucose ≥ 140mg/dl (7.7&#xD;
             mmol/l) or HbA1C &gt; 6.2%&#xD;
&#xD;
          -  Arm #3 and #4 (Parts F, G, H and I) only: history of severe cutaneous reaction (eg.&#xD;
             Stevens-Johnson syndrome [SJS], erythema multiforme [EM]), toxic epidermal necrolysis&#xD;
             (TEN), and drug reaction with eosinophilia and systemic symptoms [DRESS].&#xD;
&#xD;
          -  Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw&#xD;
&#xD;
          -  Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g.&#xD;
             viral, bacterial, fungal etc.)&#xD;
&#xD;
          -  Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis,&#xD;
             angioedema due to concomitant treatment with ACE inhibitors, impaired wounds&#xD;
&#xD;
          -  Arm #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia&#xD;
             and hyperglycemia in non-diabetic participants&#xD;
&#xD;
          -  Arm #4 (Parts H and I) only: treatment with strong or moderate CYP3A4 inhibitors,&#xD;
             strong CYP3A4 inducers and/or P-gp inhibitors within 2 weeks before the first study&#xD;
             treatment administration or 5 elimination half-lives, whichever is the longest&#xD;
&#xD;
          -  Arm #5 (Parts J and K) only: history or current (controlled/not controlled) venous&#xD;
             thromboembolism (i.e. deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral&#xD;
             venous sinus thrombosis (CVST)&#xD;
&#xD;
        The above information is not intended to contain all considerations relevant to a patient's&#xD;
        potential participation in a clinical trial.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Investigational Site Number :8400005</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80262</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8400002</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8400102</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8400003</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8400001</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560001</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240004</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240003</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 4E6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240002</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030002</name>
      <address>
        <city>Brno</city>
        <zip>65653</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030001</name>
      <address>
        <city>Praha 2</city>
        <zip>12808</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030003</name>
      <address>
        <city>Praha 4</city>
        <zip>14059</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500002</name>
      <address>
        <city>Bordeaux Cedex</city>
        <zip>33076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500005</name>
      <address>
        <city>Lille</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500003</name>
      <address>
        <city>Lyon</city>
        <zip>69373</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500001</name>
      <address>
        <city>Saint-Herblain</city>
        <zip>44805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500004</name>
      <address>
        <city>Villejuif</city>
        <zip>94800</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800002</name>
      <address>
        <city>Negrar</city>
        <state>Verona</state>
        <zip>37024</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800001</name>
      <address>
        <city>Milano</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800003</name>
      <address>
        <city>Milano</city>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800004</name>
      <address>
        <city>Napoli</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160001</name>
      <address>
        <city>Warsaw</city>
        <state>Mazowieckie</state>
        <zip>02-781</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160004</name>
      <address>
        <city>Gdynia</city>
        <state>Pomorskie</state>
        <zip>81-519</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200001</name>
      <address>
        <city>Lisboa</city>
        <zip>1649-035</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200002</name>
      <address>
        <city>Lisboa</city>
        <zip>1998-018</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200003</name>
      <address>
        <city>Porto</city>
        <zip>4200</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240007</name>
      <address>
        <city>Madrid</city>
        <state>Madrid, Comunidad De</state>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240001</name>
      <address>
        <city>Madrid</city>
        <state>Madrid, Comunidad De</state>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240002</name>
      <address>
        <city>Madrid</city>
        <state>Madrid, Comunidad De</state>
        <zip>28050</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260003</name>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <zip>OX3 7LE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260002</name>
      <address>
        <city>Cardiff</city>
        <state>Vale Of Glamorgan, The</state>
        <zip>CF14 2TL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Italy</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Korea, Democratic People's Republic of</country>
  </removed_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 15, 2017</study_first_posted>
  <last_update_submitted>January 24, 2023</last_update_submitted>
  <last_update_submitted_qc>January 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03284957
org study id: TED14856
secondary id: 2017-000690-36
secondary id: U1111-1189-4896
nct id: NCT03284957
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose Limiting Toxicities (DLTs)
time frame: Cycle 1, Day 28 for each treated participant (each cycle is 28 days)
description: 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)
measure: Objective Response Rate (ORR)
time frame: Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant
description: 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)
measure: Adverse Events
time frame: Up to 30 days after last dose of amcenestrant
description: 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)
measure: Adverse Events
time frame: Up to 30 days after last dose of amcenestrant
description: 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
measure: ORR
time frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
description: 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
measure: Time to First Response (TTR)
time frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
description: Time from the start of treatment to the first objective tumor response observed for participants who achieved CR or PR in all treatment arms
measure: Clinical Benefit Rate (CBR)
time frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
description: 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
measure: Duration of response
time frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
description: Time from initial response to the first documented tumor progression in all treatment arms
measure: tlag of amcenestrant after single dose
time frame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
description: 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)
measure: tmax of amcenestrant after single dose
time frame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arms #1, #2, #4, and #5)
measure: Cmax of amcenestrant after single dose
time frame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arms #1, #2, #4, and #5)
measure: AUC0-24 of amcenestrant after single dose
time frame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
description: 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)
measure: tmax of amcenestrant after repeated dose administration
time frame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
description: tmax is time to reach Cmax in all treatment arms
measure: Cmax of amcenestrant after repeated dose administration
time frame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
description: Cmax is maximum concentration observed in all treatment arms
measure: AUC0-24 of amcenestrant after repeated dose administration
time frame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
description: 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
measure: Ctrough of amcenestrant during repeated dose administration
time frame: Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1 (each cycle is 28 days)
description: Ctrough is plasma concentration observed just before treatment administration during repeated dosing in all treatment arms
measure: tmax of palbociclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #2)
measure: Cmax of palbociclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #2)
measure: AUC0-24 of palbociclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)
measure: tmax of palbociclib after repeated dose administration
time frame: Cycle 1, Day 21 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #2)
measure: Cmax of palbociclib after repeated dose administration
time frame: Cycle 1, Day 21 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #2)
measure: AUC0-24 of palbociclib after repeated dose administration
time frame: Cycle 1, Day 21 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #2)
measure: Urine excretion of amcenestrant
time frame: Cycle 1, Day 21 (each cycle is 28 days)
description: Urine excretion of amcenestrant during the monotherapy expansion phase (Arm #1 Part B)
measure: Cholesterol concentration ratios
time frame: Up to Cycle 2 (each cycle is 28 days)
description: Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1)
measure: ER occupancy at 18F-FES-PET imaging
time frame: Baseline and one assessment in Cycle 1 on Day 11 to 15 (each cycle is 28 days)
description: Inhibition of ER occupancy at 18F-FES-PET imaging (signal extinction) (Arm #1 Part A)
measure: Progression free survival
time frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
description: 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.
measure: Observation of tumor changes by FES PET and FDG PET scans
time frame: Baseline and approximately at Day 15 of Cycle 1 in Part A (each cycle is 28 days)
description: To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET (Arm #1 Part A)
measure: tmax of alpelisib after third dose
time frame: Cycle 1, Day 3 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #3)
measure: Cmax of alpelisib after third dose
time frame: Cycle 1, Day 3 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #3)
measure: AUC0-24 of alpelisib after third dose
time frame: Cycle 1, Day 3 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)
measure: tmax of alpelisib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #3)
measure: Cmax of alpelisib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #3)
measure: AUC0-24 of alpelisib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #3)
measure: tmax of everolimus after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #4)
measure: Cmax of everolimus after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #4)
measure: AUC0-24 of everolimus after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)
measure: tmax of everolimus after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #4)
measure: Cmax of everolimus after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #4)
measure: AUC0-24 of everolimus after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #4)
measure: tmax of abemaciclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #5)
measure: Cmax of abemaciclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #5)
measure: AUC0-24 of abemaciclib after single dose
time frame: Cycle 1, Day 1 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)
measure: tmax of abemaciclib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: tmax is time to reach Cmax (Arm #5)
measure: Cmax of abemaciclib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: Cmax is maximum concentration observed (Arm #5)
measure: AUC0-24 of abemaciclib after repeated dose administration
time frame: Cycle 1, Day 22 (each cycle is 28 days)
description: AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arm #5)
arm group label: Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion
arm group type: Experimental
description: 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.
arm group label: Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion
arm group type: Experimental
description: 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).
arm group label: Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion
arm group type: Experimental
description: 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.
arm group label: Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion
arm group type: Experimental
description: 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.
arm group label: Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Amcenestrant
description: Pharmaceutical form: capsule
Route of administration: oral
arm group label: Amcenestrant Monotherapy: Arm #1 Part A Dose Escalation, Part B Dose Expansion
arm group label: Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion
arm group label: Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion
arm group label: Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion
arm group label: Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion
other name: SAR439859
intervention type: Drug
intervention name: Palbociclib
description: Pharmaceutical form: capsule
Route of administration: oral
arm group label: Amcenestrant/Palbociclib: Arm #2 Part C Dose Escalation, Part D Dose Expansion
other name: Ibrance®
intervention type: Drug
intervention name: Alpelisib
description: Pharmaceutical form: tablet
Route of administration: oral
arm group label: Amcenestrant/Alpelisib: Arm #3 Part F Safety Run-In, Part G Dose Expansion
other name: Piqray®
intervention type: Drug
intervention name: Everolimus
description: Pharmaceutical form: tablet
arm group label: Amcenestrant/Everolimus: Arm #4 Part H Dose Escalation, Part I Dose Expansion
intervention type: Drug
intervention name: Abemaciclib
description: Pharmaceutical form: tablet
arm group label: Amcenestrant/Abemaciclib: Arm #5 Part J Dose Escalation, Part K Dose Expansion
other name: Verzenio®
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
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country: Belgium
country: Canada
country: Czechia
country: France
country: Italy
country: Poland
country: Portugal
country: Spain
country: United Kingdom
country: United States
country: Korea, Democratic People's Republic of
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Everolimus
mesh term: Palbociclib
sharing ipd: Yes
ipd description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org