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Phase 1 / 2 Study of SAR439859 Single Agent and in Combination With Palbociclib in Postmenopausal Women With Estrogen Receptor Positive Advanced Breast Cancer (AMEERA-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03284957
Recruitment Status : Recruiting
First Posted : September 15, 2017
Last Update Posted : July 28, 2020
Sponsor:
Information provided by (Responsible Party):
Sanofi

Brief Summary:

Primary Objectives:

Dose Escalation: Part A (SAR439859 monotherapy); Part C (combination of SAR439859 with palbociclib)

  • To determine the maximum tolerated dose (MTD) and recommended dose (RD) of SAR439859 based on the dose-limiting toxicity (DLT) observance in monotherapy (Part A), and in combination with palbociclib (Part C)

Dose Expansion: Part B (SAR439859 monotherapy)

  • To assess antitumor activity by Objective Response Rate (ORR) at the SAR439859 recommended dose in monotherapy

Dose Expansion: Part D (combination of SAR439859 with palbociclib)

  • Overall safety profile of SAR439859 in combination with palbociclib

Midazolam Drug-Drug Interaction Sub-Study: Part E

  • To assess the effect of SAR439859 on CYP3A enzyme activity using midazolam as a probe

Secondary Objectives:

  • Overall safety profile of SAR439859 as monotherapy (Parts A, B, E), and in combination with palbociclib (Parts C, D)
  • Pharmacokinetic (PK) profile of SAR439859 as monotherapy (Parts A, B, E), and of SAR439859 in combination with palbociclib (Parts C, D), and of palbociclib in combination with SAR439859 (Parts C, D)
  • Antitumor activity of SAR439859 as monotherapy (Part A and E), and in combination with palbociclib (Part C and D) as well as the Clinical Benefit Rate (CBR: Complete Response [CR], Partial Response [PR] and Stable Disease [SD] ≥24 weeks) in Parts A, B, C, D and E
  • ORR and CBR (CR, PR and SD ≥24 weeks) in Parts B, D and E according to the estrogen receptor 1 (ESR1) gene mutational status (mutant and wild type) at baseline and in treatment
  • Time to first tumor response (CR or PR) in Parts B and D
  • Residual estrogen receptor (ER) availability with [(18)F] Fluoroestradiol Positron Emission Tomography (FES PET) scan (Part A)
  • To assess potential induction/inhibition effect of SAR439859 on CYP3A (Part A, B, E)

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: SAR439859 Drug: palbociclib Drug: midazolam Phase 1 Phase 2

Detailed Description:
Duration of the study, per patient, 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 after the last study treatment administration (i.e. at least 30 days post last treatment or until the patient receives another anticancer therapy, whichever is earlier). The expected enrollment period is approximately 36-40 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 259 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study for the Safety, Efficacy, Pharmacokinetic and Pharmacodynamics Evaluation of SAR439859, Administered Orally as Monotherapy, Then in Combination With Palbociclib in Postmenopausal Women With Estrogen Receptor-positive Advanced Breast Cancer (AMEERA-1)
Actual Study Start Date : September 20, 2017
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Palbociclib

Arm Intervention/treatment
Experimental: Part A Dose escalation: SAR439859 monotherapy
SAR439859 will be administered orally once (QD) or twice a day (BID). Treatment will begin with an identified starting dose. Administration of higher doses to subsequent patients 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 28-day cycle.
Drug: SAR439859

Pharmaceutical form: capsule

Route of administration: oral


Experimental: Part B Dose expansion: SAR439859 monotherapy
Patients will be administered the determined monotherapy recommended dose (RD) of SAR439859. Drug will be administered in 28-day cycle.
Drug: SAR439859

Pharmaceutical form: capsule

Route of administration: oral


Experimental: Part C Dose escalation: SAR439859/palbociclib combination
SAR439859 will be administered in combination with palbociclib: SAR439859 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 SAR439859 (with standard palbociclib dose) to subsequent patients will be based on occurrence of DLTs at initial and subsequent doses, until MAD of SAR439859 is reached. Drugs will be administered in 28-day cycle (palbociclib will be administered for 21 days of cycle). If results from Part A BID indicate a benefit of BID regimen, an additional BID dose regimen could be tested in Part C.
Drug: SAR439859

Pharmaceutical form: capsule

Route of administration: oral


Drug: palbociclib

Pharmaceutical form: capsule

Route of administration: oral

Other Name: Ibrance®

Experimental: Part D Dose expansion: SAR439859/palbociclib combination

Based on the results in Part C, patients will be administered either: 1) a determined SAR439859 dose (RD) with standard dose of palbociclib in combination therapy, or 2) one of two randomized dose levels of SAR439859 with standard dose of palbociclib in combination therapy.

Drugs will be administered in 28-day cycle (palbociclib will be administered for 21 days of cycle).

Drug: SAR439859

Pharmaceutical form: capsule

Route of administration: oral


Drug: palbociclib

Pharmaceutical form: capsule

Route of administration: oral

Other Name: Ibrance®

Experimental: Part E Midazolam Drug-Drug Interaction Sub-Study
Midazolam will be administered as a single oral dose two times within Cycle 1 (Day 1 and Day 15). SAR439859 will be administered at two sequential dose levels.The PK evaluation will be done in the first 6 patients treated at the first dose level. Each dose level will be completed depending on the PK analysis of the first dose level.
Drug: SAR439859

Pharmaceutical form: capsule

Route of administration: oral


Drug: midazolam

Pharmaceutical form: solution for injection

Route of administration: oral





Primary Outcome Measures :
  1. Part A : To determine the RD of SAR439859 [ Time Frame: Cycle 1 (Day 28) for each treated patient ]
    Incidence of study treatment-related DLTs at Cycle 1

  2. Part C : To determine the RD of SAR439859 in combination with palbociclib [ Time Frame: Cycle 1 (Day 28) for each treated patient ]
    Incidence of study treatment-related DLTs at Cycle 1

  3. Part B : to evaluate the ORR of SAR439859 [ Time Frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient ]
    Proportion of patients with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by independent central reviewer relative to the total number of treated patients

  4. Part D: Adverse Events [ Time Frame: Up to 30 days after last dose of SAR439859 ]
    Number of patients 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

  5. Part E: AUClast and AUC of midazolam [ Time Frame: Cycle 1 Day 1 and Cycle 1 Day 15 ]
    Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to the real time tlast (AUClast) and AUC were assessed to determine the effect of SAR439859 on CYP3A enzyme activity


Secondary Outcome Measures :
  1. Part A, B, C, E: Adverse Events [ Time Frame: Up to 30 days after last dose of SAR439859 ]
    Number of patients 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

  2. ORR [ Time Frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient ]
    Proportion of patients with CR or PR according to RECIST 1.1 assessed by investigator/local radiologist relative to the total number of treated patients (Part A, B, C, D, E)

  3. 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 patient ]
    Time from the start of treatment to the first objective tumor response observed for patients who achieved CR or PR

  4. 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 patient ]
    Proportion of patients with CR or PR or SD ≥24 weeks according to RECIST v.1.1 relative to the total number of treated patients by investigators/local radiologists (Parts A, B, C, D and E) and by independent central reviewer (Part B)

  5. Duration of response [ Time Frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient ]
    Time from initial response to the first documented tumor progression

  6. tlag of SAR439859 after single dose (Part A, B, C, D) [ Time Frame: Cycle 1, Day 1 Part A (fasted state), B, C and D, and Day 3 Part A (fed state) ]
    tlag is interval between administration time and the sampling time preceding the first concentration above the lower limit of quantification of SAR439859

  7. tmax of SAR439859 after single dose (Part A, B, C, D) [ Time Frame: Cycle 1, Day 1 Part A (fasted state), B, C and D, and Day 3 Part A (fed state) ]
    tmax is time to reach Cmax

  8. Cmax of SAR439859 after single dose (Part A, B, C, D) [ Time Frame: Cycle 1, Day 1 Part A (fasted state), B, C and D, and Day 3 Part A (fed state) ]
    Cmax is maximum concentration observed

  9. AUC0-24 of SAR439859 after single dose (Part A, B, C, D) [ Time Frame: Cycle 1, Day 1 Part A (fasted state), B, C and D, and Day 3 Part A (fed state) ]
    AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)

  10. tmax of SAR439859 after repeated dose administration (Part A, B, C, D) [ Time Frame: Cycle 1, Day 22 ]
    tmax is time to reach Cmax

  11. Cmax of SAR439859 after repeated dose administration (Part A, B, C, D) [ Time Frame: Cycle 1, Day 22 ]
    Cmax is maximum concentration observed

  12. AUC0-24 of SAR439859 after repeated dose administration (Part A, B,C, D) [ Time Frame: Cycle 1, Day 22 ]
    AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)

  13. Ctrough of SAR439859 during repeated dose administration (Part A, B, C, D) [ Time Frame: Cycle 1, Day 3, Day 8, Day 15, Day 22 ]
    Ctrough is plasma concentration observed just before treatment administration during repeated dosing

  14. tmax of palbociclib after single dose (Part C, D) [ Time Frame: Cycle 1, Day 1 ]
    tmax is time to reach Cmax

  15. Cmax of palbociclib after single dose (Part C, D) [ Time Frame: Cycle 1, Day 1 ]
    Cmax is maximum concentration observed

  16. AUC0-24 of palbociclib after single dose (Part C, D) [ Time Frame: Cycle 1, Day 1 ]
    AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)

  17. tmax of palbociclib after repeated dose administration (Part C, D) [ Time Frame: Cycle 1, Day 22 ]
    tmax is time to reach Cmax

  18. Cmax of palbociclib after repeated dose administration (Part C, D) [ Time Frame: Cycle 1, Day 22 ]
    Cmax is maximum concentration observed

  19. AUC0-24 of palbociclib after repeated dose administration (Part C, D) [ Time Frame: Cycle 1, Day 22 ]
    AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)

  20. Urine excretion of SAR439859 (Part B) [ Time Frame: Cycle 1, Day 22 ]
    Urine excretion of SAR439859 during the monotherapy expansion phase (Part B)

  21. Cytochrome P450 3A (CYP3A) enzyme induction and inhibition (Part B) [ Time Frame: Cycle 1, Day 1 and Day 22 ]
    CYP3A enzyme induction and inhibition by SAR439859 at RD

  22. CYP3A enzyme induction and inhibition (Part A, E) [ Time Frame: Cycle 1, Day 1 and Cycle 2, Day 1 (Cycle duration=28 days) ]
    CYP3A enzyme induction and inhibition by SAR439859 at RD

  23. ER occupancy at 18FES-PET imaging (Part A) [ Time Frame: Baseline, and one assessment in Cycle 1, on Day 11 - 15 ]
    Inhibition of ER occupancy at 18FES-PET imaging (signal extinction)

  24. Non-progression rate at 6 months [ Time Frame: Part A, B, C, D and E at 6 months ]
    Percentage of patients without progression at 6 months assessed by investigators/local radiologists (Parts A, B, C, D, E) and by independent central reviewer (Part B)

  25. 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 ]
    To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET in Part A



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Parts A, B, C, D and E:

  • Patients 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
  • Patients previously treated with endocrine therapy for advanced disease: at least 6 months exposure to endocrine therapy (Patients with early progression on adjuvant endocrine therapy or who progressed on adjuvant endocrine therapy within 12 months after completion are eligible), and in part D, no more than 2 prior lines of endocrine therapy are allowed
  • Patients previously treated with chemotherapy for advanced disease: no more than 3 prior chemotherapeutic regimens in Part A, and no more than 1 prior chemotherapeutic regimen in Parts B, C, D and E (including Antibody Drug Conjugates)
  • Measurable lesion

Exclusion criteria:

  • Medical history or ongoing gastrointestinal disorders that could affect absorption of SAR439859 and/or palbociclib (including difficulties with swallowing capsules)
  • Patient 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 patient has been disease free for >3 years)
  • Patients 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) (except fulvestrant) with a washout of at least 6 weeks prior to the first study drug administration
  • Inadequate hematological and biochemical lab tests
  • Patients with Gilbert disease
  • Treatment with human immunodeficiency virus (HIV)-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts
  • Treatment with strong and moderate cytochrome P450 (CYP) 3A or CYP2C8 inducers within 2 weeks before first study treatment
  • Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment starts
  • More than one prior cyclin-dependent kinase (CDK) 4/6 inhibitor based therapy.
  • No prior CDK4/6 exposure is required for patients with early progression on adjuvant endocrine therapy or who progressed on adjuvant endocrine therapy within 12 months after completion of adjuvant endocrine therapy

Part A only:

  • Patients with liver metastases only

Part D only:

  • Prior therapy with any selective CDK4/6 inhibitor, phosphoinositide 3-kinase (PI3K) inhibitors and mammalian target of rapamycin (mTOR) inhibitors

Part E only:

  • Any treatment with weak CYP3A inducer and all CYP3A inhibitors within 2 weeks before midazolam administration
  • Any contraindications to midazolam (in accordance with the applicable label)
  • Use of any herbal medicines 1 week, and grapefruit juice for 72 hours before midazolam administration and up to the end of PK sampling following the last midazolam administration
  • Patients older than 60 years

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03284957


Contacts
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Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext 1 then # Contact-Us@sanofi.com

Locations
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Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03284957    
Other Study ID Numbers: TED14856
2017-000690-36 ( EudraCT Number )
U1111-1189-4896 ( Other Identifier: UTN )
First Posted: September 15, 2017    Key Record Dates
Last Update Posted: July 28, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data (IPD) and supporting clinical documents are available for request at clinicalstudydatarequest.com. While making information available Sanofi continues to protect the privacy of the participants in clinical trials and to remove commercially confidential information (CCI). Details on Data Sharing criteria and process for requesting access can be found at this web address: clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Palbociclib
Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors