Clinical Trials /

Phase 1 / 2 Study of SAR439859 Single Agent and in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor Positive Advanced Breast Cancer

NCT03284957

Description:

Primary Objectives: Dose Escalation: Part A (SAR439859 monotherapy); Part C (combination of SAR439859 with palbociclib); Part F (Safety-Run-In - combination of SAR439859 with alpelisib): -To determine the maximum tolerated dose (MTD) and recommended dose (RD) of SAR439859 based on the dose-limiting toxicity observance in monotherapy (Part A) and in combination with palbociclib (Part C), and to confirm the combination RD with alpelisib (Part F). 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) and Part G (combination of SAR439859 with alpelisib): -Overall safety profile of SAR439859 in combination with palbociclib or alpelisib Secondary Objectives: - Overall safety profile of SAR439859 as monotherapy (Parts A,B), in combination with palbociclib (Part C) or in combination with alpelisib (Part F) - Pharmacokinetic (PK) profile of SAR439859 as monotherapy (Parts A,B), in combination with palbociclib (Parts C,D), in combination with alpelisib (Parts F,G), and PK of palbociclib (Parts C,D) and alpelisib (Parts F,G) alone and/or with SAR439859 - Antitumor activity of SAR439859 as monotherapy (Part A), in combinations with palbociclib (Part C,D) or alpelisib (F,G), and Clinical Benefit Rate (CBR: CR, PR and SD≥24 weeks) in Parts A,B,C,D,F,G - ORR and CBR in Parts B, D and G per estrogen receptor 1 (ESR1) gene mutational status (mutant and wild type) at baseline and in treatment - Time to 1st response (CR,PR) (Part B,D,G) - Residual 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)

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1 / 2 Study of SAR439859 Single Agent and in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor Positive Advanced Breast Cancer
  • 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 Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor-positive Advanced Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: TED14856
  • SECONDARY ID: 2017-000690-36
  • SECONDARY ID: U1111-1189-4896
  • NCT ID: NCT03284957

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
SAR439859Part A Dose escalation: SAR439859 monotherapy
palbociclibIbrance®Part C Dose escalation: SAR439859/palbociclib combination
alpelisibPiqray®Part F Safety Run-In: SAR439859/alpelisib combination

Purpose

Primary Objectives: Dose Escalation: Part A (SAR439859 monotherapy); Part C (combination of SAR439859 with palbociclib); Part F (Safety-Run-In - combination of SAR439859 with alpelisib): -To determine the maximum tolerated dose (MTD) and recommended dose (RD) of SAR439859 based on the dose-limiting toxicity observance in monotherapy (Part A) and in combination with palbociclib (Part C), and to confirm the combination RD with alpelisib (Part F). 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) and Part G (combination of SAR439859 with alpelisib): -Overall safety profile of SAR439859 in combination with palbociclib or alpelisib Secondary Objectives: - Overall safety profile of SAR439859 as monotherapy (Parts A,B), in combination with palbociclib (Part C) or in combination with alpelisib (Part F) - Pharmacokinetic (PK) profile of SAR439859 as monotherapy (Parts A,B), in combination with palbociclib (Parts C,D), in combination with alpelisib (Parts F,G), and PK of palbociclib (Parts C,D) and alpelisib (Parts F,G) alone and/or with SAR439859 - Antitumor activity of SAR439859 as monotherapy (Part A), in combinations with palbociclib (Part C,D) or alpelisib (F,G), and Clinical Benefit Rate (CBR: CR, PR and SD≥24 weeks) in Parts A,B,C,D,F,G - ORR and CBR in Parts B, D and G per estrogen receptor 1 (ESR1) gene mutational status (mutant and wild type) at baseline and in treatment - Time to 1st response (CR,PR) (Part B,D,G) - Residual 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)

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 42 months.
    

Trial Arms

NameTypeDescriptionInterventions
Part A Dose escalation: SAR439859 monotherapyExperimentalSAR439859 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.
  • SAR439859
Part B Dose expansion: SAR439859 monotherapyExperimentalPatients will be administered the determined monotherapy recommended dose (RD) of SAR439859. Drug will be administered in 28-day cycle.
  • SAR439859
Part C Dose escalation: SAR439859/palbociclib combinationExperimentalSAR439859 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.
  • SAR439859
  • palbociclib
Part D Dose expansion: SAR439859/palbociclib combinationExperimentalBased 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).
  • SAR439859
  • palbociclib
Part F Safety Run-In: SAR439859/alpelisib combinationExperimentalSAR439859 will be administered in combination with alpelisib at a fixed standard dose. Additional dose levels of SAR439859 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 SAR439859 and alpelisib will be administered in 28-day cycle.
  • SAR439859
  • alpelisib
Part G Dose expansion: SAR439859/alpelisib combinationExperimentalBased on the conclusion in Part F, patients will be administered the determined RD of SAR439859 and alpelisib given in the combination in an expansion cohort (Part G). Both study drugs will be administered in 28-day cycle.
  • SAR439859
  • alpelisib

Eligibility Criteria

        Inclusion criteria:

        Parts A, B, C, D, F and G:

          -  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 relapse while on adjuvant
             endocrine therapy that was intitiated ≥24 months ago, or who relapsed < 12 months
             after completion of adjuvant endocrine therapy are eligible); in Part D, no more than
             2 prior lines of endocrine therapy are allowed; in Parts F and G, patients must have
             received and progressed on Aromatase Inhibitor (AI) in combination with CDK4/6
             Inhibitor as the first line (1L) treatment for advanced disease prior to receiving the
             study treatment, and not followed by further endocrine therapy for advanced disease
             before entering the study.

          -  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 F (including Antibody Drug Conjugates)

          -  Measurable lesion

        Exclusion criteria:

          -  Medical history or ongoing gastrointestinal disorders that could affect absorption of
             oral study drugs (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. No
             prior fulvestrant (or any other SERD)(Parts F, G).

          -  Inadequate hematological and biochemical lab tests

          -  Patients with Gilbert disease

          -  Treatment with 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 advanced cyclin-dependent kinase (CDK) 4/6 inhibitor based
             therapy.

        Part F and G only:

          -  Patients with current pneumonitis

          -  Prior therapy with chemotherapy (Part G) and therapies that target the
             phosphoinositide 3-kinase (PI3K) axis: mammalian target of rapamycin (mTOR)
             infibitors, AKT inhibitors, PI3K inhibitors (Part F and G)

          -  Patients with Diabetes Mellitus Type-I or uncontrolled Diabetes Mellitus Type-II

          -  History of Severe Cutaneous Reaction (Stevens-Johnson syndrome [SJS], erythema
             multiforme [EM], toxic epidermal necrolysis [TEN], drug reaction with eosinophilia and
             systemic symptoms [DRESS])

          -  Ongoing jaw osteonecrosis

        The above information is not intended to contain all considerations relevant to a patient's
        potential participation in a clinical trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: To determine the RD of SAR439859
Time Frame:Cycle 1 (Day 28) for each treated patient
Safety Issue:
Description:Incidence of study treatment-related DLTs at Cycle 1

Secondary Outcome Measures

Measure:Part A, B, C and F: Adverse Events
Time Frame:Up to 30 days after last dose of SAR439859
Safety Issue:
Description: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
Measure:ORR
Time Frame:Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient
Safety Issue:
Description: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, F, G)
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 patient
Safety Issue:
Description:Time from the start of treatment to the first objective tumor response observed for patients who achieved CR or PR
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 patient
Safety Issue:
Description: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, F, G) and by independent central reviewer (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 patient
Safety Issue:
Description:Time from initial response to the first documented tumor progression
Measure: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)
Safety Issue:
Description:tlag is interval between administration time and the sampling time preceding the first concentration above the lower limit of quantification of SAR439859
Measure: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)
Safety Issue:
Description:tmax is time to reach Cmax
Measure: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)
Safety Issue:
Description:Cmax is maximum concentration observed
Measure: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)
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Measure:tmax of SAR439859 after repeated dose administration (Part A, B, C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:tmax is time to reach Cmax
Measure:Cmax of SAR439859 after repeated dose administration (Part A, B, C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:Cmax is maximum concentration observed
Measure:AUC0-24 of SAR439859 after repeated dose administration (Part A, B, C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Measure:Ctrough of SAR439859 during repeated dose administration (Part A, B, C, D)
Time Frame:Cycle 1, Day 3, Day 8, Day 15, Day 22
Safety Issue:
Description:Ctrough is plasma concentration observed just before treatment administration during repeated dosing
Measure:tmax of palbociclib after single dose (Part C, D)
Time Frame:Cycle 1, Day 1
Safety Issue:
Description:tmax is time to reach Cmax
Measure:Cmax of palbociclib after single dose (Part C, D)
Time Frame:Cycle 1, Day 1
Safety Issue:
Description:Cmax is maximum concentration observed
Measure:AUC0-24 of palbociclib after single dose (Part C, D)
Time Frame:Cycle 1, Day 1
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Measure:tmax of palbociclib after repeated dose administration (Part C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:tmax is time to reach Cmax
Measure:Cmax of palbociclib after repeated dose administration (Part C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:Cmax is maximum concentration observed
Measure:AUC0-24 of palbociclib after repeated dose administration (Part C, D)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Measure:Urine excretion of SAR439859 (Part B)
Time Frame:Cycle 1, Day 22
Safety Issue:
Description:Urine excretion of SAR439859 during the monotherapy expansion phase (Part B)
Measure:Cytochrome P450 3A (CYP3A) enzyme induction and inhibition (Part B)
Time Frame:Cycle 1, Day 1 and Day 22
Safety Issue:
Description:CYP3A enzyme induction and inhibition by SAR439859 at RD
Measure:CYP3A enzyme induction and inhibition (Part A)
Time Frame:Cycle 1, Day 1 and Cycle 2, Day 1 (each cycle is 28 days)
Safety Issue:
Description:CYP3A enzyme induction and inhibition by SAR439859 at RD
Measure:ER occupancy at 18FES-PET imaging (Part A)
Time Frame:Baseline, and one assessment in Cycle 1, on Day 11 - 15
Safety Issue:
Description:Inhibition of ER occupancy at 18FES-PET imaging (signal extinction)
Measure:Non-progression rate at 6 months
Time Frame:Part A, B, C, D at 6 months
Safety Issue:
Description:Percentage of patients without progression at 6 months assessed by investigators/local radiologists (Parts A, B, C, D) and by independent central reviewer (Part B)
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
Safety Issue:
Description:To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET in Part A
Measure:tmax of alpelisib after third dose (Part F, G)
Time Frame:Cycle 1, Day 3 (each cycle is 28 days)
Safety Issue:
Description:tmax is time to reach Cmax
Measure:Cmax of alpelisib after third dose (Part F, G)
Time Frame:Cycle 1, Day 3 (each cycle is 28 days)
Safety Issue:
Description:Cmax is maximum concentration observed
Measure:AUC0-24 of alpelisib after third dose (Part F, G)
Time Frame:Cycle 1, Day 3 (each cycle is 28 days)
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Measure:tmax of alpelisib after repeated dose administration (Part F, G)
Time Frame:Cycle 1, Day 22 (each cycle is 28 days)
Safety Issue:
Description:tmax is time to reach Cmax
Measure:Cmax of alpelisib after repeated dose administration (Part F, G)
Time Frame:Cycle 1, Day 22 (each cycle is 28 days)
Safety Issue:
Description:Cmax is maximum concentration observed
Measure:AUC0-24 of alpelisib after repeated dose administration (Part F, G)
Time Frame:Cycle 1, Day 22 (each cycle is 28 days)
Safety Issue:
Description:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sanofi

Last Updated

February 10, 2021