Cancer MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Code: SAR439859
Pharmaceutical Form: Capsule, hard
Current Sponsor code: SAR439859
Concentration unit: mg milligram(s)
Concentra
Sponsors
SANOFI-AVENTIS RECHERCHE ET DEVELOPPEMENT
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 160 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 120
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 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 Objective: - Overall safety profile of SAR439859 as monotherapy (Parts A, B, E), and in combination with palbociclib (Part C). - 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: CR, PR and 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 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). ; | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1: Up to 30 days after last dose of SAR439859 2/3/4/5 : Baseline to the date of first documentation of progression, assessed approximatively up to 6 months after the last entered patient 6/7: Cycle 1, Day 1 Part A (fasted state), B, C and D, and Day 3 Part A (fed state) for tlag, tmax, Cmax and AUC0-24 and Cycle 1, Day 22 for tmax and Cmax 8: Cycle 1, Day 22 for AUC0-24 and Cycle 1, Day 3, Day 8, Day 15, Day 22 for Ctrough 9: Cycle 1, D 1 10: Cycle 1, D 22 11: Cycle 1, Day 22 for Urine excretion - Cycle 1, Day 1 and Day 22 and Cycle 1, Day 1 and Cycle 2, Day 1 (Cycle duration=28 days) for CYP3A 12 : Baseline, and one assessment in Cycle 1, on Day 11 - 15 for Inhibition of ER occupancy and Part A, B, C, D and E at 6 months 13: Baseline and approximately at D15 of Cycle 1 in part A ; Secondary end point(s): 1/ Adverse Events - 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 - 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 from the start of treatment to the first objective tumor response observed for patients who achieved CR or PR 4/ Clinical Benefit Rate (CBR) - 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 | — |
Countries
Belgium, Canada, Czech Republic, France, Italy, Poland, Portugal, Spain, United Kingdom, United States
Contacts
Public ContactMedical Information
SANOFI-AVENTIS RECHERCHE ET DEVELOPPEMENT
Outcome results
None listed