Breast CancerPhase 3BioItaLEENCT03439046

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

A Phase 3 study testing Ribociclib, Letrozole and Alpelisib in people with Breast Cancer, run by Novartis Pharmaceuticals at 41 sites in Italy.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Breast Cancer
What is being tested?: Ribociclib, Letrozole and Alpelisib
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 287 participants
Where: 41 sitesItaly
Study dates: 2 Feb 2018to 11 Dec 2023
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
No healthy volunteers
Adult, Older adult

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.

Trial locations and contacts

41 sites in 1 country.

City, postcode or hospital

41 sites in 1 country

Italy41 sites

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

Other trials in Italy

About this study

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)

Read the 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.

Conditions: Breast Cancer
Being tested: Ribociclib, Letrozole, Alpelisib, Fulvestrant
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
Medical subject headings: Breast Neoplasms, Hereditary Sensory and Autonomic Neuropathies

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RibociclibDrug
Also called LEE011
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
LetrozoleDrug
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
AlpelisibDrug
Also called BYL719
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
FulvestrantDrug
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

Study groups in NCT03439046
Study group	Role	What they receive
ribociclib+letrozole	Experimental	Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD Receives: Drug: Ribociclib; Drug: Letrozole
alpelisib+fulvestrant	Experimental	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 Receives: Drug: Alpelisib; Drug: Fulvestrant

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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%.
Measured: 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.
Measured: Up to approximately 1.6 years

Secondary outcomes (14)

Percent Change From Screening in Thymidine Kinase 1 (TK1) Serum Level
Measured: 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.
Measured: 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.
Measured: 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%.
Measured: 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%.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: Up to approximately 5.7 years
Change From Baseline Tumor Microenvironment Parameters to Progression of Disease During the Core and Extension Phases
Measured: Up to approximately 5.7 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

2 Feb 201811 Dec 2023

First posted20 Feb 2018
Study start2 Feb 2018
Primary completion11 Dec 2023
Study completion11 Dec 2023

Why it stopped: Novartis terminated the trial early because the collected data were sufficient to perform the analysis stated for the primary endpoint.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Breast CancerStudies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Enrolment: 287 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03439046
Sponsor's protocol ID: CLEE011AIT01
Other IDs: 2017-004176-62, 2017
Acronym: BioItaLEE
Status last verified: Jun 2026
First submitted: 29 Jan 2018
Last updated: 10 Jul 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 10 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT03439046
Acronym / sponsor ID: BioItaLEE / CLEE011AIT01
Conditions: Breast Cancer
Keywords: HR-positive HER2-negative, advanced breast cancer, LEE011, ribociclib, letrozole, CDK, CDK4, CDK6
Phase: Phase 3
Study type: Interventional
Recruitment status: TerminatedReason stopped: Novartis terminated the trial early because the collected data were sufficient to perform the analysis stated for the primary endpoint.
Enrolment: 287 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 2 Feb 2018 (actual)
Primary completion: 11 Dec 2023 (actual)
Study completion: 11 Dec 2023 (actual)
First posted: 20 Feb 2018 (actual)
Results: Posted 10 Jul 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
ribociclib+letrozole	Experimental	Drug: Ribociclib, Drug: LetrozoleRibociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
alpelisib+fulvestrant	Experimental	Drug: Alpelisib, Drug: FulvestrantAlpelisib 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

Who may qualify

Ages: 18 years and older
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RibociclibAlso: LEE011Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD	Drug	ribociclib+letrozole
LetrozoleRibociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD	Drug	ribociclib+letrozole
AlpelisibAlso: BYL719Alpelisib 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+fulvestrant
FulvestrantAlpelisib 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+fulvestrant

Primary outcome

Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change
Time frame: Up to approximately 5.7 years
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.
Number of Participants With Progression-Free Survival (PFS) Events by Cycle 1 Day 15 Complete Mutational Dynamic Change
Time frame: Up to approximately 5.7 years
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.
Number of Participants With Hotspot Mutated Genes by Scheduled Timepoint
Time frame: Up to approximately 5.7 years
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.
Percent Change From Screening in Target Mutation Variant Allele Frequency (VAF)
Time frame: Up to approximately 5.7 years
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%.
Number of Participants With Partial Response (PR) in the Extension Phase
Time frame: Up to approximately 1.6 years
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.

14 secondary outcomes

Percent Change From Screening in Thymidine Kinase 1 (TK1) Serum Level
Time frame: Up to approximately 5.7 years
Number of Long Responder Participants With Hotspot Mutated Genes by Scheduled Timepoint
Time frame: Up to approximately 5.7 years
Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint
Time frame: Up to approximately 5.7 years
Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders
Time frame: Up to approximately 5.7 years
Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors
Time frame: Up to approximately 5.7 years
Number of Screening Hotspot Mutations Per De Novo Patient in Liquid Biopsy Samples and Tissue Samples
Time frame: Up to approximately 5.7 years
Number of Screening Hotspot Mutations Per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples
Time frame: 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
Time frame: 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
Time frame: Up to approximately 5.7 years
Time to Progression (TTP)
Time frame: 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)
Time frame: Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
Percentage of Participants With Clinical Benefit Rate
Time frame: 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
Time frame: Up to approximately 5.7 years
Change From Baseline Tumor Microenvironment Parameters to Progression of Disease During the Core and Extension Phases
Time frame: Up to approximately 5.7 years

Results and safety

Results posted to the registry on 10 Jul 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Ribociclib+Letrozole (Core Phase)	287	184
Alpelisib+Fulvestrant (Extension Phase)	0	0

Primary outcome: Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change

Time frame: Up to approximately 5.7 years. Median (95% Confidence Interval). Unit: months

Measure	Ribociclib+Letrozole (Core Phase) n = 187
Persistent Wild Type n=76	55.82 (39.06 to NA)
New Mutated n=19	16.53 (9.03 to 45.90)
Late Mutated n=8	15.67 (2.00 to 21.42)
Confirmed Cleared n=46	22.44 (15.93 to 32.23)
Unconfirmed Cleared n=8	10.22 (2.69 to NA)
Late Cleared n=12	11.07 (3.29 to 19.09)
Confirmed Mutated n=18	14.32 (2.89 to 44.22)

Population analysed: The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants who had a valid sample at screening, Cycle 1 Day 15, Cycle 2 Day 1, and at the first imaging evaluation. Each cycle was 28 days.

Primary outcome: Number of Participants With Progression-Free Survival (PFS) Events by Cycle 1 Day 15 Complete Mutational Dynamic Change

Time frame: Up to approximately 5.7 years. Number. Unit: participants

Measure	Ribociclib+Letrozole (Core Phase) n = 187
Persistent Wild Type n=76	31
New Mutated n=19	13
Late Mutated n=8	6
Confirmed Cleared n=46	28
Unconfirmed Cleared n=8	6
Late Cleared n=12	10
Confirmed Mutated n=18	12

Primary outcome: Number of Participants With Hotspot Mutated Genes by Scheduled Timepoint

Time frame: Up to approximately 5.7 years. Number. Unit: participants

Measure	Ribociclib+Letrozole (Core Phase) n = 263
None at Screening n=263	145
None at Cycle 1 Day 15 n=238	152
None at Cycle 2 Day 1 n=242	160
None at First Imaging Evaluation n=206	147
None at End of Study Treatment due to PD n=118	50
None at End of Study Treatment due to Other n=39	27
One at Screening n=263	70
One at Cycle 1 Day 15 n=238	51

Primary outcome: Percent Change From Screening in Target Mutation Variant Allele Frequency (VAF)

Time frame: Up to approximately 5.7 years. Median (Full Range). Unit: percent change

Measure	Ribociclib+Letrozole (Core Phase) n = 263
Cycle 1, Day 15 n=104	-94.33 (-100.0 to 134.5)
Cycle 2, Day 1 n=106	-100.00 (-100.0 to 167.8)
First Imaging Evaluation n=90	-100.00 (-100.0 to 1110.9)
End of Treatment due to PD n=66	-47.48 (-100.0 to 1133.9)
End of treatment due to other n=16	-100.00 (-100.0 to 29.8)

14 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 5.8 years in the core phase and 1.7 years in the extension phase.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Ribociclib+Letrozole (Core Phase)	79 of 287 (27.5%)	275 of 287 (95.8%)	27 of 287
Alpelisib+Fulvestrant (Extension Phase)	6 of 21 (28.6%)	20 of 21 (95.2%)	3 of 21

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

41 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ribociclib, Letrozole and Alpelisib in people with Breast Cancer, run by Novartis Pharmaceuticals at 41 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 10 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 41 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jul 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change (time frame: Up to approximately 5.7 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03439046.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2026.