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

• Status: Recruiting
• Trial end date: 2024-01-01
• Target enrollment: 0
• Participant gender: Female

Summary

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

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Sanofi
• Treatments: Estrogens; Everolimus; Palbociclib

Criteria

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 previously treated with endocrine therapy for advanced disease: at least 6 months exposure to endocrine therapy (Participants with early relapse while on adjuvant endocrine therapy that was initiated ≥24 months ago, or who relapsed < 12 months after completion of adjuvant endocrine therapy are eligible); in Arm #2 Part D, no more than 2 prior lines of endocrine therapy are allowed; in Arm #3 Parts F and G, participants must have received and progressed on Aromatase Inhibitor (AI) in combination with CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease prior to receiving the study treatment, and not followed by additional endocrine therapy for advanced disease before entering the study; for Arm #4 (Parts H and I) and Arm #5 (J and K): no more than 1 prior line of a single endocrine therapy for advanced disease is allowed or for Arm #4 Parts H and I: participants must have received and progressed on a non-steroidal Aromatase Inhibitor (AI) in combination with a CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease prior to receiving the study treatment; For Arms #2, #3,#4, and #5 (Parts C, D, F, G, H, I, J and K) participants who relapsed while on adjuvant endocrine therapy that was initiated ≥24 months ago, or relapsed < 12 months after completion of adjuvant endocrine therapy are eligible.

• 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), except fulvestrant with a washout of at least 6 weeks prior to the first study drug administration. In Arms #3, #4, and #5 (Parts F, G, H, I, J 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 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 advanced cyclin-dependent kinase (CDK) 4/6 inhibitor based therapy in Arm #1 (Parts A and B), Arm #2 (Part C), and Arm #3 (Parts F and G)

• 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) 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.