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

Phase 3TerminatedNCT03439046

Novartis Pharmaceuticals287 enrolled

Overview

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

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

287

Conditions

Breast Cancer

Interventions

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (41)

Novartis Investigative Site

Casale Monferrato, AL, Italy

Novartis Investigative Site

Bari, BA, Italy

Novartis Investigative Site

Bergamo, BG, Italy

Novartis Investigative Site

Benevento, BN, Italy

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Outcomes

Primary Outcomes

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.