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

NCT03439046 | Terminated Phase 3 Results

• 2 other identifiers: CLEE011AIT012017-004176-62
• Study Type: interventional
• Target: 287
• Locations: 1 country
• Sites: 41

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

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (14)

• 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

  Up to approximately 5.7 years

• Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint

  Up to approximately 5.7 years

• Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders

  Up to approximately 5.7 years

• Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors

  Up to approximately 5.7 years

Study Arms (2)

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

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

Drug: Alpelisib; Drug: Fulvestrant

Interventions

Ribociclib DRUG

Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

Also known as: LEE011

ribociclib+letrozole

Letrozole DRUG

Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

ribociclib+letrozole

Alpelisib DRUG

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

Also known as: BYL719

alpelisib+fulvestrant

Fulvestrant DRUG

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

alpelisib+fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (41)

Novartis Investigative Site

Casale Monferrato, AL, 15033, Italy

Location

Novartis Investigative Site

Bari, BA, 70124, Italy

Location

Novartis Investigative Site

Bergamo, BG, 24127, Italy

Location

Novartis Investigative Site

Benevento, BN, 82100, Italy

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Brindisi, BR, 72100, Italy

Location

Novartis Investigative Site

Brescia, BS, 25123, Italy

Location

Novartis Investigative Site

Cremona, CR, 26100, Italy

Location

Novartis Investigative Site

Catania, CT, 95123, Italy

Location

Novartis Investigative Site

Catania, CT, 95124, Italy

Location

Novartis Investigative Site

Cona, FE, 44100, Italy

Location

Novartis Investigative Site

San Giovanni Rotondo, FG, 71013, Italy

Location

Novartis Investigative Site

Genova, GE, 16132, Italy

Location

Novartis Investigative Site

Livorno, LI, 57124, Italy

Location

Novartis Investigative Site

Monza, MB, 20900, Italy

Location

Novartis Investigative Site

Province of Macerata, MC, 62100, Italy

Location

Novartis Investigative Site

Messina, ME, 98158, Italy

Location

Novartis Investigative Site

Milan, MI, 20132, Italy

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Milan, MI, 20141, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Nuoro, NU, 08100, Italy

Location

Novartis Investigative Site

Palermo, PA, 90127, Italy

Location

Novartis Investigative Site

Palermo, PA, 90146, Italy

Location

Novartis Investigative Site

Padova, PD, 35100, Italy

Location

Novartis Investigative Site

Perugia, PG, 06129, Italy

Location

Novartis Investigative Site

Pisa, PI, 56126, Italy

Location

Novartis Investigative Site

Aviano, PN, 33081, Italy

Location

Novartis Investigative Site

Prato, PO, 59100, Italy

Location

Novartis Investigative Site

Fano, PU, 61032, Italy

Location

Novartis Investigative Site

Faenza, RA, 48018, Italy

Location

Novartis Investigative Site

Roma, RM, 00128, Italy

Location

Novartis Investigative Site

Roma, RM, 00168, Italy

Location

Novartis Investigative Site

Roma, RM, 00189, Italy

Location

Novartis Investigative Site

Salerno, SA, 84131, Italy

Location

Novartis Investigative Site

Candiolo, TO, 10060, Italy

Location

Novartis Investigative Site

Torino, TO, 10128, Italy

Location

Novartis Investigative Site

Udine, UD, 33100, Italy

Location

Novartis Investigative Site

Negrar, VR, 37024, Italy

Location

Novartis Investigative Site

Naples, 80131, Italy

Location

Novartis Investigative Site

Naples, 80138, Italy

Location

MeSH Terms

Conditions

Breast Neoplasms; Hereditary Sensory and Autonomic Neuropathies

Interventions

ribociclib; Letrozole; Alpelisib; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2018
• First Posted: February 20, 2018
• Study Start: February 2, 2018
• Primary Completion: December 11, 2023
• Study Completion: December 11, 2023
• Last Updated: July 10, 2026
• Results First Posted: July 10, 2026

Record last verified: 2026-06

Locations

IT (41)