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)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 287
- 试验地点
- 42
- 主要终点
- Change from baseline ctDNA alterations to progression disease during Core and Extension Phase
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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 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.
排除标准
- •Patient who received prior treatment with any CDK4/6 inhibitor.
- •Patient who received any prior systemic hormonal therapy or chemotherapy for advanced breast cancer.
- •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.
研究组 & 干预措施
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
干预措施: Ribociclib (Drug)
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
干预措施: Alpelisib (Drug)
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
干预措施: Fulvestrant (Drug)
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
干预措施: Letrozole (Drug)
结局指标
主要结局
Change from baseline ctDNA alterations to progression disease during Core and Extension Phase
时间窗: 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.
Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- The percentage of patients with ctDNA alterations will be provided over time in the subsets during Core and Extension Phase(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 serum TK1 concentrations to progression disease during core phase(Up to approximately 36 months starting from Baseline of the core phase)
- The percentage of patients with mutations as assessed at baseline of the Core and Extension phase across different patient profiles(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(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(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(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(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(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(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(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(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)
- Percentage of Participants With Clinical Benefit Rate(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)
- 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)
- Number of Screening Hotspot Mutations Per De Novo Patient in Liquid Biopsy Samples and Tissue Samples(Up to approximately 5.7 years)
- Number of Screening Hotspot Mutations Per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples(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(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(Up to approximately 5.7 years)
- Time to Progression (TTP)(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)(Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years)