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)
Overview
- Phase
- Phase 3
- Intervention
- Ribociclib
- Conditions
- Breast Cancer
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 287
- Locations
- 1
- Primary Endpoint
- Change from baseline ctDNA alterations to progression disease during Core and Extension Phase
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
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.
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.
- •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.
Arms & Interventions
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
Intervention: Ribociclib
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
Intervention: Letrozole
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
Intervention: Alpelisib
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
Intervention: Fulvestrant
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- 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)