| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
- 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). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 |
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| E.4 | Principal 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1/ Part A : To determine the RD of SAR439859 - Incidence of study treatment-related DLTs at Cycle 1
2/ Part C : To determine the RD of SAR439859 in combination with palbociclib - Incidence of study treatment-related DLTs at Cycle 1
3/ Part B : to evaluate the ORR of SAR439859 - Proportion of patients with CR or PR according to RECIST 1.1 assessed by independent central reviewer relative to the total number of treated patients
4/ Part D: 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
5/ Part E: AUClast and AUC of midazolam - 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1/2 : Cycle 1 (Day 28) for each treated patient
3 : Baseline to the date of first documentation of progression, assessed approximatively up to 6 months after the last entered patient
4 : Up to 30 days after last dose of SAR439859
5 : Cycle 1 Day 1 and Cycle 1 Day 15. |
|
| E.5.2 | 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 response - Time from initial response to the first documented tumor progression
6/ tlag of SAR439859 after single dose (Part A, B, C, D) - tlag is interval between administration time and the sampling time preceding the first concentration above the lower limit of quantification of SAR439859 tmax of SAR439859 after single dose (Part A, B, C, D) - tmax is time to reach Cmax
Cmax of SAR439859 after single dose (Part A, B, C, D) - Cmax is maximum concentration observed
7/ AUC0-24 of SAR439859 after single dose (Part A, B, C, D) - AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) tmax of SAR439859 after repeated dose administration (Part A, B, C, D) - tmax is time to reach Cmax
Cmax of SAR439859 after repeated dose administration - Cmax is maximum concentration observed
8/ AUC0-24 of SAR439859 after repeated dose administration (Part A, B,C, D) - AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
Ctrough of SAR439859 during repeated dose administration - Ctrough is plasma concentration observed just before treatment administration during repeated dosing
9/ tmax of palbociclib after single dose (Part C, D) - tmax is time to reach Cmax
Cmax of palbociclib after single dose (Part C, D) - Cmax is maximum concentration observed AUC0-24 of palbociclib after single dose (Part C, D) - 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 palbociclib after repeated dose administration (Part C, D) - tmax is time to reach Cmax
Cmax of palbociclib after repeated dose administration (Part C, D) - Cmax is maximum concentration observed
AUC0-24 of palbociclib after repeated dose administration (Part C, D) - AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours)
11/ Urine excretion of SAR439859 (Part B) - Urine excretion of SAR439859 during the monotherapy expansion phase (Part B) CYP3A enzyme induction and inhibition (Part B) - CYP3A enzyme induction and inhibition by SAR439859 at RD CYP3A enzyme induction and inhibition (Part A, E) - CYP3A enzyme induction and inhibition by SAR439859 at RD
12/ ER occupancy at 18FES-PET imaging (Part A) - Inhibition of ER occupancy at 18FES-PET imaging (signal extinction) Non-progression rate at 6 months - Percentage of patients without progression at 6 months assessed by investigators/local radiologists (Parts A, B, C, D and E) and by independent central reviewer (Part B)
13/ Observation of tumor changes by FES PET and FDG PET scans – To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET in Part A |
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| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Dose escalation and expansion |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Italy |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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