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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-09-15
Enrollment: 136
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed description: 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.

Eligibility 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 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.

Primary outcomes:
measure: Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1, Day 28 for each treated participant (each cycle is 28 days)
measure: Objective Response Rate (ORR)
timeFrame: Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant
measure: Adverse Events
timeFrame: Up to 30 days after last dose of amcenestrant
Secondary outcomes:
measure: Adverse Events
timeFrame: Up to 30 days after last dose of amcenestrant
measure: ORR
timeFrame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
measure: Time to First Response (TTR)
timeFrame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
measure: Clinical Benefit Rate (CBR)
timeFrame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
measure: Duration of response
timeFrame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
measure: tlag of amcenestrant after single dose
timeFrame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
measure: tmax of amcenestrant after single dose
timeFrame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
measure: Cmax of amcenestrant after single dose
timeFrame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
measure: AUC0-24 of amcenestrant after single dose
timeFrame: Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
measure: tmax of amcenestrant after repeated dose administration
timeFrame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
measure: Cmax of amcenestrant after repeated dose administration
timeFrame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
measure: AUC0-24 of amcenestrant after repeated dose administration
timeFrame: Cycle 1, Day 21 or 22 (each cycle is 28 days)
measure: Ctrough of amcenestrant during repeated dose administration
timeFrame: Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1 (each cycle is 28 days)
measure: tmax of palbociclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: Cmax of palbociclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: AUC0-24 of palbociclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: tmax of palbociclib after repeated dose administration
timeFrame: Cycle 1, Day 21 (each cycle is 28 days)
measure: Cmax of palbociclib after repeated dose administration
timeFrame: Cycle 1, Day 21 (each cycle is 28 days)
measure: AUC0-24 of palbociclib after repeated dose administration
timeFrame: Cycle 1, Day 21 (each cycle is 28 days)
measure: Urine excretion of amcenestrant
timeFrame: Cycle 1, Day 21 (each cycle is 28 days)
measure: Cholesterol concentration ratios
timeFrame: Up to Cycle 2 (each cycle is 28 days)
measure: ER occupancy at 18F-FES-PET imaging
timeFrame: Baseline and one assessment in Cycle 1 on Day 11 to 15 (each cycle is 28 days)
measure: Progression free survival
timeFrame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
measure: Observation of tumor changes by FES PET and FDG PET scans
timeFrame: Baseline and approximately at Day 15 of Cycle 1 in Part A (each cycle is 28 days)
measure: tmax of alpelisib after third dose
timeFrame: Cycle 1, Day 3 (each cycle is 28 days)
measure: Cmax of alpelisib after third dose
timeFrame: Cycle 1, Day 3 (each cycle is 28 days)
measure: AUC0-24 of alpelisib after third dose
timeFrame: Cycle 1, Day 3 (each cycle is 28 days)
measure: tmax of alpelisib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: Cmax of alpelisib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: AUC0-24 of alpelisib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: tmax of everolimus after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: Cmax of everolimus after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: AUC0-24 of everolimus after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: tmax of everolimus after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: Cmax of everolimus after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: AUC0-24 of everolimus after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: tmax of abemaciclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: Cmax of abemaciclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: AUC0-24 of abemaciclib after single dose
timeFrame: Cycle 1, Day 1 (each cycle is 28 days)
measure: tmax of abemaciclib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: Cmax of abemaciclib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
measure: AUC0-24 of abemaciclib after repeated dose administration
timeFrame: Cycle 1, Day 22 (each cycle is 28 days)
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado- Site Number : 8400005
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital Site Number : 8400002
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center- Site Number : 8400003
state: New York
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance- Site Number : 8400001
state: Washington
city: Leuven
country: Belgium
facility: Investigational Site Number : 0560001
city: Edmonton
country: Canada
facility: Investigational Site Number : 1240004
state: Alberta
city: Vancouver
country: Canada
facility: Investigational Site Number : 1240003
state: British Columbia
city: Toronto
country: Canada
facility: Investigational Site Number : 1240002
state: Ontario
city: Brno
country: Czechia
facility: Investigational Site Number : 2030002
city: Praha 2
country: Czechia
facility: Investigational Site Number : 2030001
city: Praha 4
country: Czechia
facility: Investigational Site Number : 2030003
city: Bordeaux Cedex
country: France
facility: Investigational Site Number : 2500002
city: Lille
country: France
facility: Investigational Site Number : 2500005
city: Lyon
country: France
facility: Investigational Site Number : 2500003
city: Saint-Herblain
country: France
facility: Investigational Site Number : 2500001
city: Villejuif
country: France
facility: Investigational Site Number : 2500004
city: Milano
country: Italy
facility: Investigational Site Number : 3800003
city: Gdynia
country: Poland
facility: Investigational Site Number : 6160004
state: Pomorskie
city: Lisboa
country: Portugal
facility: Investigational Site Number : 6200001
city: Lisboa
country: Portugal
facility: Investigational Site Number : 6200002
city: Madrid
country: Spain
facility: Investigational Site Number : 7240007
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Investigational Site Number : 7240002
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Investigational Site Number : 7240001
city: Oxford
country: United Kingdom
facility: Investigational Site Number : 8260003
state: Oxfordshire
city: Cardiff
country: United Kingdom
facility: Investigational Site Number : 8260002
state: Vale Of Glamorgan, The
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Bardia A, Chandarlapaty S, Linden HM, Ulaner GA, Gosselin A, Cartot-Cotton S, Cohen P, Doroumian S, Paux G, Celanovic M, Pelekanou V, Ming JE, Ternes N, Bouaboula M, Lee JS, Bauchet AL, Campone M. AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer. Nat Commun. 2022 Jul 15;13(1):4116. doi: 10.1038/s41467-022-31668-8.