Breast Cancer
Conditions
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
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.
Interventions
DRUGRibociclib
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
DRUGLetrozole
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
DRUGAlpelisib
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
DRUGFulvestrant
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
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change | 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 | 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 | 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) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint | Up to approximately 5.7 years | 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. |
| Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders | 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%. |
| Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors | 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 Screening Hotspot Mutations Per De Novo Patient in Liquid Biopsy Samples and Tissue Samples | Up to approximately 5.7 years | 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. |
| Number of Screening Hotspot Mutations Per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples | Up to approximately 5.7 years | 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. |
| Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at Screening | Up to approximately 5.7 years | 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). |
| Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at End of Treatment | Up to approximately 5.7 years | 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). |
| Time to Progression (TTP) | Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years | 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. |
| Percentage of Participants With Best Overall Response Rate of Complete Response (CR) or Partial Response (PR) | Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years | 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. |
| Percentage of Participants With Clinical Benefit Rate | Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years | 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. |
| 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 | — |
Countries
Italy
Participant flow
Pre-assignment details
All inclusion and exclusion criteria were checked at screening.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 8.39 |
| Age, Customized 0 - <28 days | 0 participants |
| Age, Customized 12 years - <18 years | 0 participants |
| Age, Customized 18 years - <65 years | 125 participants |
| Age, Customized 28 days - <2 years | 0 participants |
| Age, Customized 2 years - <12 years | 0 participants |
| Age, Customized 65 years - <85 years | 161 participants |
| Age, Customized >=85 years | 1 participants |
| Age, Customized in utero | 0 participants |
| Age, Customized Preterm newborns infants | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Caucasian | 280 participants |
| Race/Ethnicity, Customized Other Race | 1 participants |
| Race/Ethnicity, Customized Unknown Race | 5 participants |
| Sex: Female, Male Female | 287 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 287 | 3 / 21 |
| other Total, other adverse events | 275 / 287 | 20 / 21 |
| serious Total, serious adverse events | 79 / 287 | 6 / 21 |
Outcome results
None listed