| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To determine whether SAR439859 per os improves progression free survival (PFS) when compared with a endocrine monotherapy of the choice of the physician, in participants with metastatic or locally advanced breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the overall survival in the 2 treatment arms.
- To assess the objective response rate in the 2 treatment arms.
- To evaluate the disease control rate in the 2 treatment arms.
- To evaluate the clinical benefit rate in the 2 treatment arms.
- To evaluate the duration of response in the 2 treatment arms.
- To evaluate the PFS according to the estrogen receptor 1 gene (ESR1) mutation status in the 2 treatment arms.
- To evaluate the pharmacokinetics of SAR439859 as single agent.
- To evaluate health related quality of life in the 2 treatment arms.
- To compare the overall safety profile in the 2 treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 18 years or older
- Histological or cytological diagnosis of adenocarcinoma of the breast.
- Locally advanced not amenable to radiation therapy or surgery in a curative intent, and/or metastatic disease.
- ER positive status
- HER2 negative status
- Participants must have received no more than 1 prior chemotherapeutic or 1 targeted therapy regimen for advanced/metastatic disease.
- In the main study, a prior treatment with a CDK 4/6 inhibitor is mandatory if this treatment is approved and can be reimbursed for this participant. The percentage of participants without previous CDK 4/6 inhibitor will be capped to 20%. In the Chinese extension cohort, previous treatment with a CDK 4/6 inhibitor will not be mandatory, and there will be no limitation to the number of participants naïve to CDK4/6 inhibitor.
- Participants must present a secondary endocrine resistance to endocrine therapy defined as: progression while on endocrine therapy after at least 6 months of treatment for advanced breast cancer, or relapse while on adjuvant endocrine therapy but after the first 2 years, or with a relapse within 12 months after completing adjuvant endocrine therapy.
- Male or Female. |
|
| E.4 | Principal exclusion criteria |
- Eastern Cooperative Oncology Group performance status ≥2.
- Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of SAR439859. Participants unable to swallow normally and to take capsules.
- Participant with any other cancer. Adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or any other cancer from which the participant has been disease free for >3 years are allowed.
- Severe uncontrolled systemic disease at screeening.
- Participants with known brain metastases that are untreated, symptomatic or require therapy to control symptoms.
- Prior treatment with mammalian target of rapamycin inhibitors or any other selective estrogen receptor degrader (SERD) compound, except fulvestrant if stopped for at least 3 months before randomization.
- Treatment with drugs that have the potential to inhibit UGT less than 2 weeks before randomization .
- Treatment with strong or moderate CYP3A/CYP2C8 inducers within 2 weeks before randomization.
- Ongoing treatment with drugs that are substrate of P-glycoprotein (P gp) (dabigatran, digoxin, fexofenadine).
- Treatment with anticancer agents (including investigational drugs) less than 3 weeks before randomization.
- Inadequate hematological, coagulation, renal and liver functions. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS): PFS is defined as the time interval from the date of randomization to the date of documented tumor progression as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or death (due to any cause), whichever comes first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 18 months after the first randomized participant |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS): OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause)
2. Objective Response Rate (ORR): ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR), as best overall response determined by RECIST 1.1 from the date of randomization to the date of end of treatment
3. Disease Control Rate (DCR): DCR is defined as the proportion of participants who have a confirmed CR, PR, or stable disease (SD) determined by RECIST 1.1 from the date of randomization to the date of end of treatment
4. Clinical Benefit Rate (CBR): CBR is defined as the proportion of participants who have a confirmed CR, PR, or stable disease (SD) for at least 24 weeks determined by RECIST 1.1 from the date of randomization to the date of end of treatment
5. Duration of Response (DOR): DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) as determined by objective radiographic disease assessment per RECIST 1.1 or death from any cause, whichever occurs first
6. PFS according to (ESR1) mutation status: PFS as per the estrogen receptor 1 (ESR1) mutation status determined at study entry
7. Assessments of the Pharmacokinetic (PK) of SAR439859 as single agent : Plasma Concentrations. SAR439859 plasma concentrations
8. Patient Reported Outcome (PRO) - health-related quality of life and health status using the European Quality of Life-5 Dimensions (EQ-5D): EQ-5D is a standardized measure of health status
9. Patient Reported Outcome (PRO) - the European Organisation for Research and Treatment of Cancer core quality of life questionnaire (EORTC-QLQ-C30): The EORTC-QLQ-C30 is composed of both multi item scales and single item measures. These include 5 functional scales, 3 symptom scales, a Global Health Status (GHS)/quality of life scale, and 6 single item
10. Patient Reported Outcome (PRO) - EORTC-QLQ breast cancer (EORTC-QLQ-BR23): The EORTC-QLQ-BR23 contains 23 items: 8 assessing function and 15 items assessing symptoms of disease or treatment
11. Overall safety profile -Treatment-Emergent Adverse events: Number of participants with treatment-emergent adverse events (TEAEs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 64 months after first randomized participant
2, 3. Up to 18 months after the first randomized participant
4. From the date of randomization to the date of end of treatment
5, 6. Up to 18 months after the first randomized participant
7. Day 1 and Day 15 of Cycle 1 and Day 1 of Cycles 3, 4 and 6 (each cycle is 28 days)
8, 9, 10. Day 1 of Cycle 1 and day 1 of subsequent cycle every 2 cycles up to to 30 days after last study treatment (each cycle is 28 days)
11. Evaluated continuously throughout study from the date of enrollment, up to 30 days after last study treatment administration |
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Greece |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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