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)

February 22, 2024 updated by: Novartis Pharmaceuticals

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

Completed

Conditions

Intervention / Treatment

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

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Napoli, Italy, 80131
        • Novartis Investigative Site
      • Napoli, 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
      • Macerata, MC, Italy, 62100
        • Novartis Investigative Site
    • ME
      • Messina, ME, Italy, 98158
        • Novartis Investigative Site
    • MI
      • Milano, MI, Italy, 20133
        • Novartis Investigative Site
      • Milano, MI, Italy, 20132
        • Novartis Investigative Site
      • Milano, MI, Italy, 20141
        • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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
Change from baseline ctDNA alterations to progression disease during Core and Extension Phase
Time Frame: 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
The percentage of patients with ctDNA alterations (i.e. such as but not limited to Rb, ESR1, cyclin D1, CDKN2A, PIK3CA, p53 and PTEN) will be provided over time to characterize the biological evolution of the disease in each patient. The association of these alterations with clinical outcomes will also be provided.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline serum TK1 concentrations to progression disease during core phase
Time Frame: Up to approximately 36 months starting from Baseline of the core phase
Descriptive statistics of serum TK1 concentrations will be provided over time. The association/correlation of serum TK1 concentrations with clinical outcomes will also be provided.
Up to approximately 36 months starting from Baseline of the core phase
The percentage of patients with ctDNA alterations will be provided over time in the subsets during Core and Extension Phase
Time Frame: 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
The percentage of patients with ctDNA alterations will be provided over time in the subsets of long responder patients and those with early progression
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
Change from baseline tumor mutational burden (TMB) to progression disease during Core and Extension Phase
Time Frame: 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
Descriptive statistics of tumor mutational burden (TMB), defined as a quantitative measure of the total number of ctDNA mutations per coding area of tumor genome, will be provided over time, according to the scheduled sample collections. The association of TMB values with clinical outcomes will also be provided.
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
The percentage of patients with mutations as assessed at baseline of the Core and Extension phase across different patient profiles
Time Frame: Screening Core Phase and Screening Extension Phase
The percentage of patients with mutations as assessed at baseline by means of ctDNA sample, and tissue biopsy will be compared between the following patient profiles defined according to disease history (i.e. newly diagnosed vs. recurrent disease).
Screening Core Phase and Screening Extension Phase
The percentage of patients with alterations detected through liquid biopsy vs. tissue biopsy during Core and Extension Phase
Time Frame: 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
The percentage of patients with alterations detected at baseline and at disease progression will be compared between the two different procedures of detection (i.e. detection through liquid biopsy vs. tissue biopsy).
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
Change from baseline tumor microenvironment parameters to progression disease during Core and Extension Phase
Time Frame: 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
Descriptive statistics of tumor microenvironment parameters on tumor biopsy will be provided at baseline and upon disease progression. The association of these tumor micro-environment parameters with clinical outcomes will also be provided.
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
Time-to-Progression (TTP) during Core and Extension Phase
Time Frame: 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
Time to progression (TTP) is 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.
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
The number of patients with adverse events as a measure of safety and tolerability during Core and Extension Phase
Time Frame: 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
Fequency and severity of AEs and SAEs
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
The percentage of patients with best overall response rate CR or PR during Core and Extension Phase
Time Frame: 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
Overall response rate (ORR) is defined as the percentage of patients, with measurable disease, that showed best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1.
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
The percentage of patients with clinical benefit during Core and Extension Phase
Time Frame: 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
Clinical benefit rate (CBR) is defined as the percentage of patients 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. CR, PR and SD are defined according to RECIST 1.1.
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
The percentage of participants with adverse events as a measure of safety and tolerability during Core and Extension Phase
Time Frame: 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
Frequency and severity of AEs and SAEs
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

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)

February 23, 2024

Last Update Submitted That Met QC Criteria

February 22, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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