Description:
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)
Title
- Brief Title: Phase 1 / 2 Study of SAR439859 Single Agent and in Combination With Palbociclib 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 Palbociclib 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
Interventions
| Drug | Synonyms | Arms |
|---|
| SAR439859 | | Part C Dose escalation: SAR439859/palbociclib combination |
| palbociclib | Ibrance® | Part C Dose escalation: SAR439859/palbociclib combination |
Purpose
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:
- To characterize the overall safety profile of SAR439859 as monotherapy (Parts A and B),
and in combination with palbociclib (Parts C and D)
- To characterize the pharmacokinetic (PK) profile of SAR439859 as monotherapy (Parts A
and B), and of SAR439859 in combination with palbociclib (Parts C and D), as well as of
palbociclib in combination with SAR439859 (Parts C and D)
- To evaluate antitumor activity of SAR439859 as monotherapy (Part A), and in combination
with palbociclib (Part C) as well as the disease control rate (DCR) in Parts A, B, C,
and D
- To evaluate ORR and DCR (Complete Response [CR], Partial Response [PR] and Stable
Disease [SD] ≥6 months) in Parts B and D according to the estrogen receptor 1 (ESR1)
gene mutational status (mutant and wild type)
- To evaluate residual estrogen receptor (ER) availability with [(18)F] Fluoroestradiol
Positron Emission Tomography (FES PET) scan (Part A)
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Part A Dose escalation: SAR439859 monotherapy | Experimental | SAR439859 will be administered orally once a day. 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 is administered in 28-day cycle. | |
| Part B Dose expansion: SAR439859 monotherapy | Experimental | Patients will be administered the determined monotherapy recommended dose (RD) of SAR439859. Drug is administered in 28-day cycle. | |
| Part C Dose escalation: SAR439859/palbociclib combination | Experimental | 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 are administered in 28-day cycle (palbociclib is administered for 21 days of cycle). | |
| Part D Dose expansion: SAR439859/palbociclib combination | Experimental | Patients will be administered the determined SAR439859/palbociclib combination therapy RD of SAR439859, with standard dose of palbociclib. Drugs are administered in 28-day cycle (palbociclib is administered for 21 days of cycle). | |
Eligibility 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 with 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.
| 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: | 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 relative to the total number of treated patients (Part A, C) |
| Measure: | Disease Control Rate (DCR) |
| 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 >6 months according to RECIST v.1.1 relative to the total number of treated patients |
| 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 (Part B) |
| 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) (Part A) |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Sanofi |
Last Updated
September 25, 2017
