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

A Phase 1/2 Study for the Safety, Efficacy, Pharmacokinetic and Pharmacodynamics Evaluation of Amcenestrant (SAR439859), Administered Orally as Monotherapy, Then in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor-positive Advanced Breast Cancer

Primary Objectives:

Dose Escalation:

• To assess the incidence rate of dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) as well as the recommended dose (RD) of amcenestrant administered as monotherapy and in combination with palbociclib
• To assess the incidence rate of DLT and determine the RD of everolimus or abemaciclib in combination with the selected amcenestrant dose for the combination therapy

Safety Run-In:

- To confirm the RD of amcenestrant in combination with alpelisib

Dose Expansion:

• Antitumor activity using objective response rate (ORR)
• Overall safety profile of amcenestrant administered in combination with palbociclib, alpelisib, everolimus, and abemaciclib

Secondary Objectives:

• Overall safety profile of amcenestrant monotherapy and in combination
• Pharmacokinetic (PK) profile of amcenestrant administered as monotherapy or in combination and PK profile of palbociclib, alpelisib, everolimus and abemaciclib
• Antitumor activity using ORR, the clinical benefit rate (CBR) and progression free survival (PFS)
• Time to first tumor response
• Residual ER availability with positron emission tomography (PET) scan [(18)F] fluoroestradiol (18F-FES) uptake with increasing doses of amcenestrant
• Food effect on PK of amcenestrant
• Potential induction/inhibition effect of amcenestrant on cytochrome P450 (CYP) 3A using 4b-OH cholesterol

Duration of the study, per participant, 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 at least 22 to 30 days (or until the participant receives another anticancer therapy, whichever is earlier) following the last study treatment administration. The expected enrollment period is approximately 60 months.

Inclusion criteria:

• Participants 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
• Participants must have been previously treated with at least 6 months of endocrine therapy for advanced disease:
• Dose Escalation study parts:

Arm #3 - Part F and Arm #5 - Part J: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy Arm #4 -H: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy (exemestane not allowed)

- Dose Expansion study parts: Arm #2: - Part D: no more than 2 prior lines of advanced endocrine therapy for advanced disease are allowed Arm #3, - Part G: patients must have received and progressed on the combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first line (1L) treatment for advanced disease Arm #4 - Part I: participants must have received and progressed on the combination of Aromatase Inhibitors (AI) +CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease (exemestane not allowed) Arm#5: - Part K: up to 1 prior line of a single endocrine therapy for advanced disease Note: Additional patients who relapsed while on previous adjuvant endocrine therapy that was initiated ≥24 months ago, or relapsed < 12 months after completion of adjuvant endocrine therapy are also allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J and K).

• Participants previously treated with chemotherapy for advanced disease: no more than 3 prior chemotherapeutic regimens in Arm #1 Part A, and no more than 1 prior chemotherapeutic regimen in Arms #1, #2, #3, #4, and #5 (Parts B, C, D, F, H and J respectively); prior chemotherapy for advanced disease is not allowed in dose expansion of Arms #3, #4, and #5 (Part G, I and K respectively).
• Measurable lesion

Exclusion criteria:

• Medical history or ongoing gastrointestinal disorders that could affect absorption of oral study drugs (including difficulties with swallowing capsules)
• Participants 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 participant has been disease free for >3 years)
• Participants 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)
• Dose Escalation study parts (Parts F, H and J): SERDs are not allowed except for fulvestrant which will need a washout of at least 6 weeks prior to the first study drug administration
• Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD including fulvestrant will not be allowed
• Inadequate hematological and biochemical lab tests
• Participants with Gilbert disease
• Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts
• Treatment with strong P450 (CYP) 3A inducers within 2 weeks before first study treatment
• Treatment with OATP1B1/B3 sensitive substrates and which cannot be replaced
• Arm#2 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 in Arm #1, Arm #2 (Part C), Arm #3 (Parts F and G), and Arm#4 (Part H).
• Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: participants with concurrent or history of pneumonitis
• Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment therapies that target the PI3K axis (mTOR inhibitors, AKT inhibitors, PI3K inhibitors)
• Arm #3 and #4 (Parts F, G, H and I) only: participants with diabetes mellitus type-I or uncontrolled diabetes mellitus type-II: ie, fasting plasma glucose ≥ 140mg/dl (7.7 mmol/l) or HbA1C > 6.2%
• Arm #3 and #4 (Parts F, G, H and I) only: history of severe cutaneous reaction (eg. Stevens-Johnson syndrome [SJS], erythema multiforme [EM]), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms [DRESS].
• Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw
• Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g. viral, bacterial, fungal etc.)
• Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis, angioedema due to concomitant treatment with ACE inhibitors, impaired wounds
• Arm #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia and hyperglycemia in non-diabetic participants
• Arm #4 (Parts H and I) only: treatment with strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers and/or P-gp inhibitors within 2 weeks before the first study treatment administration or 5 elimination half-lives, whichever is the longest
• Arm #5 (Parts J and K) only: history or current (controlled/not controlled) venous thromboembolism (i.e. deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST)

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.