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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

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ClinicalTrials.gov Identifier: NCT03284957
Recruitment Status : Recruiting
First Posted : September 15, 2017
Last Update Posted : February 18, 2019
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); Part D (combination SAR439859 with palbociclib)

  • To assess antitumor activity by Objective Response Rate (ORR) at the SAR439859 recommended dose in monotherapy (Part B), and in combination with palbociclib (Part D)

Secondary Objectives:

  • Overall safety profile of SAR439859 as monotherapy (Parts A, B), and in combination with palbociclib (Parts C, D)
  • Pharmacokinetic (PK) profile of SAR439859 as monotherapy (Parts A, B), 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 in combination with palbociclib (Part C) 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, and D
  • ORR and CBR (CR, PR and SD ≥24 weeks) 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)

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: SAR439859 Drug: palbociclib 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 26 months.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Non-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
Actual Study Start Date : September 20, 2017
Estimated Primary Completion Date : October 21, 2020
Estimated Study Completion Date : October 21, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Part A Dose escalation: SAR439859 monotherapy
SAR439859 is administered orally once a day. Treatment has begun 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 is 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 is 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).
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
Patients will be administered the determined SAR439859/palbociclib combination therapy RD of SAR439859, with standard dose of palbociclib. 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®




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 : to evaluate the ORR of SAR439859 administered in combination with palbociclib [ 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


Secondary Outcome Measures :
  1. 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)

  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 and D) 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 (Part B)

  22. 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) (Part A)

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

  24. 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.


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 and D:

  • Patients must be postmenopausal women
  • Histological diagnosis of breast adenocarcinoma
  • Locally advanced or metastatic disease
  • Measurable disease
  • Previously treated for advanced disease
  • Either primary tumor or any metastatic site to be positive for Estrogen Receptors (ER+) and negative for human epidermal growth factor receptor 2 (HER2-) by immunohistochemistry (IHC)

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 and endometrial disorders
  • 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)
  • 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 CYP3A inducers/inhibitors within 2 weeks before first study treatment

Part A only:

  • Patients with liver metastases only

Parts C and D only:

  • Prior therapy with any selective cyclin-dependent kinase (CDK) 4/6 inhibitor
  • Treatment with strong and moderate CYP3A inducers or strong CYP3A inhibitors within 2 weeks before first study treatment starts
  • Medical conditions requiring concomitant medications that are metabolized by CYP3A

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

Locations
United States, Colorado
Investigational Site Number 8400005 Recruiting
Denver, Colorado, United States, 80262
United States, Massachusetts
Investigational Site Number 8400002 Recruiting
Boston, Massachusetts, United States, 02114
United States, New York
Investigational Site Number 8400003 Recruiting
New York, New York, United States, 10065
United States, Texas
Investigational Site Number 8400007 Recruiting
Round Rock, Texas, United States, 78665
United States, Washington
Investigational Site Number 8400001 Recruiting
Seattle, Washington, United States, 98109
Belgium
Investigational Site Number 0560001 Recruiting
Leuven, Belgium, 3000
Investigational Site Number 0560002 Recruiting
Wilrijk, Belgium, 2610
Czechia
Investigational Site Number 2030002 Recruiting
Brno, Czechia, 65653
Investigational Site Number 2030001 Recruiting
Praha 2, Czechia, 12808
Investigational Site Number 2030003 Recruiting
Praha 4, Czechia, 14059
France
Investigational Site Number 2500002 Recruiting
Bordeaux Cedex, France, 33076
Investigational Site Number 2500005 Recruiting
Lille, France, 59020
Investigational Site Number 2500003 Recruiting
Lyon, France, 69373
Investigational Site Number 2500001 Recruiting
Nantes, France, 44093
United Kingdom
Investigational Site Number 8260002 Recruiting
Cardiff, United Kingdom, CF14 2TL
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03284957     History of Changes
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: February 18, 2019
Last Verified: February 2019
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

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Estrogens
Palbociclib
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action