Clinical trial NCT03439046: Study of the Molecular Features of Postmenopausal Women With HR+ HER2-negative aBC on First-line Treatment With Ribociclib and Letrozole and, in Patients With a PIK3CA Mutation, on Second-line Treatment With Alpelisib Plus Fulvestrant
Official title: A Phase IIIb, Open-label, Local, Multicenter Study of the Molecular Features of Postmenopausal Women With Hormone Receptor-positive (HR+) HER2-negative Advanced Breast Cancer on First-line Treatment With Ribociclib Plus Letrozole and, in Patients With a PIK3CA Mutation, on Second-line Treatment With Alpelisib Plus Fulvestrant (BioItaLEE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: HR-positive HER2-negative
advanced breast cancer
LEE011
ribociclib
letrozole
CDK
CDK4
CDK6
CDK4/6
Phase IIIb
ER-positive
PR-positive
postmenopausal
biomarker
ctDNA
liquid biopsy
PIK3CA
alpelisib
fulvestrant
BYL719
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-02-20
Enrollment: 287
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this clinical trial is to study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib and letrozole and, in patients with a PIK3CA mutation, on second-line treatment with alpelisib plus fulvestrant

Detailed description: The main purpose of this local, multicenter study is to investigate genetic and gene expression alterations in tumor prior to and following progression on ribociclib, during core phase and then prior to and following progression on alpelisib and thus identify patterns of mutations, how they evolve, and their association with CDK4/6 inhibition and outcomes such as sustained response or early progression. The study also aims to evaluate pharmacogenomics and its association with adverse events (frequency and severity), drug-drug interactions and clinical outcomes.

Finally, the study will also generate additional long-term safety and efficacy data in this specific Italian population.

Eligibility criteria: CORE PHASE Inclusion Criteria:

* Patient has an advanced (locoregionally recurrent or metastatic) breast cancer in first line treatment (treatment naïve for the advanced setting).
* Patient is in post-menopause, defined by one of the following:
* Prior bilateral oophorectomy
* Age ≥60
* Age \<60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
* Patient has a histologically and/or cytologically confirmed diagnosis of estrogenreceptor positive and/or progesterone receptor positive breast cancer by local laboratory.
* Patient has an HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
* Patient is willing to undergo blood and tumor sample collection for the biological assessments/objectives as scheduled in the protocol.

CORE PHASE Exclusion Criteria:

* Patient who received prior treatment with any CDK4/6 inhibitor.
* Patient who received any prior systemic hormonal therapy or chemotherapy for advanced breast cancer.

Note:

Patients who received neo/adjuvant therapy for breast cancer are eligible. If the prior neo/adjuvant therapy included letrozole or anastrozole, the disease-free interval must be greater than 12 months from the completion of treatment until study entry.

• Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.

- Patient is currently using other anti-cancer therapy. Other protocol-defined inclusion/exclusion criteria may apply.

EXTENSION PHASE Inclusion criteria:

* Patient has been discontinued (any reason allowed) from treatment with ribociclib + letrozole in the core phase and is deemed suitable for treatment with alpelisib + fulvestrant in second line. Ribociclib + letrozole must be the last treatment regimen before alpelisib + fulvestrant.
* Patient has PIK3CA mutation as determined in tumor tissue and/or plasma by a Novartis designated laboratory. Results of tissue samples obtained during the core phase (screening or EOT) are acceptable

EXTENSION PHASE Exclusion criteria:

* Patient has received prior treatment with any PI3K inhibitors.
* Patient is concurrently using other anti-cancer therapy. Ribociclib and letrozole used in the core phase must be discontinued at least 7 days prior to day one of the extension study treatment.

All drugs with overlapping toxicities must be discontinued within 7 days and AE resolved to NCI CTCAE v4.03 Grade ≤1 prior to study treatment. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.

Primary outcomes:
measure: Change from baseline ctDNA alterations to progression disease during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
Secondary outcomes:
measure: Change from baseline serum TK1 concentrations to progression disease during core phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase
measure: The percentage of patients with ctDNA alterations will be provided over time in the subsets during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: Change from baseline tumor mutational burden (TMB) to progression disease during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: The percentage of patients with mutations as assessed at baseline of the Core and Extension phase across different patient profiles
timeFrame: Screening Core Phase and Screening Extension Phase
measure: The percentage of patients with alterations detected through liquid biopsy vs. tissue biopsy during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: Change from baseline tumor microenvironment parameters to progression disease during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: Time-to-Progression (TTP) during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: The number of patients with adverse events as a measure of safety and tolerability during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: The percentage of patients with best overall response rate CR or PR during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: The percentage of patients with clinical benefit during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
measure: The percentage of participants with adverse events as a measure of safety and tolerability during Core and Extension Phase
timeFrame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase
Other outcomes:
Locations:
city: Casale Monferrato
country: Italy
facility: Novartis Investigative Site
state: AL
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Benevento
country: Italy
facility: Novartis Investigative Site
state: BN
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Brindisi
country: Italy
facility: Novartis Investigative Site
state: BR
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Cremona
country: Italy
facility: Novartis Investigative Site
state: CR
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Cona
country: Italy
facility: Novartis Investigative Site
state: FE
city: San Giovanni Rotondo
country: Italy
facility: Novartis Investigative Site
state: FG
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Livorno
country: Italy
facility: Novartis Investigative Site
state: LI
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Macerata
country: Italy
facility: Novartis Investigative Site
state: MC
city: Messina
country: Italy
facility: Novartis Investigative Site
state: ME
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Nuoro
country: Italy
facility: Novartis Investigative Site
state: NU
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Aviano
country: Italy
facility: Novartis Investigative Site
state: PN
city: Prato
country: Italy
facility: Novartis Investigative Site
state: PO
city: Fano
country: Italy
facility: Novartis Investigative Site
state: PU
city: Faenza
country: Italy
facility: Novartis Investigative Site
state: RA
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Salerno
country: Italy
facility: Novartis Investigative Site
state: SA
city: Candiolo
country: Italy
facility: Novartis Investigative Site
state: TO
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Udine
country: Italy
facility: Novartis Investigative Site
state: UD
city: Negrar
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
Study officials:
References: