Clinical Trial · NCT03284957

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

Overview

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

Sponsor

SOFIE

Phase

Phase 1/2

Contacts

Clinical Sciences & Operations (STUDY_DIRECTOR)

ClinicalTrials.gov

NCT03284957

Drug / Compound

fluoroestradiol

Isotope(s):

Target(s):

Estrogen Receptor

Ligand Class: Small Molecules

Eligibility

Inclusion

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 must be postmenopausal women
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:
Histological diagnosis of breast adenocarcinoma
Measurable lesion
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).
Locally advanced or metastatic disease

Exclusion

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)
Inadequate hematological and biochemical lab tests
Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g. viral, bacterial, fungal etc.)
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
Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts
Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD including fulvestrant will not be allowed
Treatment with OATP1B1/B3 sensitive substrates and which cannot be replaced
Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis, angioedema due to concomitant treatment with ACE inhibitors, impaired wounds
Medical history or ongoing gastrointestinal disorders that could affect absorption of oral study drugs (including difficulties with swallowing capsules)
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 #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 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 #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.
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 #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 #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia and hyperglycemia in non-diabetic participants
Prior treatment with another selective ER down-regulator (SERD)
Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw
Arm#2 Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment starts
Participants with known brain metastases
Participants with Gilbert disease
Treatment with strong P450 (CYP) 3A inducers within 2 weeks before first study treatment