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 (BioItaLEE)

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)

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

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Ribociclib; Drug: Letrozole; Drug: Alpelisib; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 287
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80131
    • Novartis Investigative Site
  • Naples, Italy, 80138
    • Novartis Investigative Site
  • AL
    • Casale Monferrato, AL, Italy, 15033
      • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • BN
    • Benevento, BN, Italy, 82100
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BR
    • Brindisi, BR, Italy, 72100
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • CR
    • Cremona, CR, Italy, 26100
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95124
      • Novartis Investigative Site
    • Catania, CT, Italy, 95123
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44100
      • Novartis Investigative Site
  • FG
    • San Giovanni Rotondo, FG, Italy, 71013
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • LI
    • Livorno, LI, Italy, 57124
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MC
    • Province of Macerata, MC, Italy, 62100
      • Novartis Investigative Site
  • ME
    • Messina, ME, Italy, 98158
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
    • Milan, MI, Italy, 20141
      • Novartis Investigative Site
    • Milan, MI, Italy, 20132
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • NU
    • Nuoro, NU, Italy, 08100
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
    • Palermo, PA, Italy, 90146
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35100
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06129
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56126
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
  • PO
    • Prato, PO, Italy, 59100
      • Novartis Investigative Site
  • PU
    • Fano, PU, Italy, 61032
      • Novartis Investigative Site
  • RA
    • Faenza, RA, Italy, 48018
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
    • Roma, RM, Italy, 00128
      • Novartis Investigative Site
    • Roma, RM, Italy, 00189
      • Novartis Investigative Site
  • SA
    • Salerno, SA, Italy, 84131
      • Novartis Investigative Site
  • TO
    • Candiolo, TO, Italy, 10060
      • Novartis Investigative Site
    • Torino, TO, Italy, 10128
      • Novartis Investigative Site
  • UD
    • Udine, UD, Italy, 33100
      • Novartis Investigative Site
  • VR
    • Negrar, VR, Italy, 37024
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ribociclib+letrozole; Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD	Drug: Ribociclib; Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD; Other Names: LEE011; Drug: Letrozole; Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
Experimental: alpelisib+fulvestrant; Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle	Drug: Alpelisib; Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle; Other Names: BYL719; Drug: Fulvestrant; Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change	PFS: Time (months) from start of the study treatment to first documented progression or death due to any cause, whichever came first. Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.	Up to approximately 5.7 years
Number of Participants With Progression-Free Survival (PFS) Events by Cycle 1 Day 15 Complete Mutational Dynamic Change	Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.	Up to approximately 5.7 years
Number of Participants With Hotspot Mutated Genes by Scheduled Timepoint	Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. The data row labels below refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.	Up to approximately 5.7 years
Percent Change From Screening in Target Mutation Variant Allele Frequency (VAF)	The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.	Up to approximately 5.7 years
Number of Participants With Partial Response (PR) in the Extension Phase	PR was assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1, criteria and was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the screening sum of diameters.	Up to approximately 1.6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Screening in Thymidine Kinase 1 (TK1) Serum Level		Up to approximately 5.7 years
Number of Long Responder Participants With Hotspot Mutated Genes by Scheduled Timepoint	Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.	Up to approximately 5.7 years
Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint	Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.	Up to approximately 5.7 years
Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders	The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.	Up to approximately 5.7 years
Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors	The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.	Up to approximately 5.7 years
Number of Screening Hotspot Mutations Per De Novo Patient in Liquid Biopsy Samples and Tissue Samples	Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.	Up to approximately 5.7 years
Number of Screening Hotspot Mutations Per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples	Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.	Up to approximately 5.7 years
Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at Screening	Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes).	Up to approximately 5.7 years
Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at End of Treatment	Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes).	Up to approximately 5.7 years
Time to Progression (TTP)	Time to progression (TTP) was defined as time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer.	Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
Percentage of Participants With Best Overall Response Rate of Complete Response (CR) or Partial Response (PR)	ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
Percentage of Participants With Clinical Benefit Rate	Clinical benefit rate (CBR) was defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. Per RECIST v. 1.1, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.	Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
Change From Baseline Tumor Mutational Burden (TMB) to Progression of Disease During the Core and Extension Phases		Up to approximately 5.7 years
Change From Baseline Tumor Microenvironment Parameters to Progression of Disease During the Core and Extension Phases		Up to approximately 5.7 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2018
• Primary Completion (Actual): December 11, 2023
• Study Completion (Actual): December 11, 2023

Study Registration Dates

• First Submitted: January 29, 2018
• First Submitted That Met QC Criteria: February 13, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: biomarker; LEE011; BYL719; PIK3CA; ribociclib; postmenopausal; ctDNA; advanced breast cancer; liquid biopsy; letrozole; CDK4/6; CDK4; CDK6; fulvestrant; CDK; HR-positive HER2-negative; Phase IIIb; ER-positive; PR-positive; alpelisib
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Skin Diseases; Breast Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Breast Neoplasms; Hereditary Sensory and Autonomic Neuropathies; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Nitriles; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Triazoles; Letrozole; Fulvestrant; ribociclib; Alpelisib
• Other Study ID Numbers: CLEE011AIT01; 2017-004176-62 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No