Abstract OT3-1-05: Phase I, open-label study evaluating the safety and tolerability of LJM716, BYL719 and trastuzumab in patients with metastatic HER2+ breast cancer
Authors: Shah Payal D , Chandarlapaty Sarat , Ulaner Gary , Zamora Stephen , Sterlin Valentina , Iasonos Alexia , Dickler Maura N , Moynahan Mary Ellen , Hudis Clifford A , Baselga Jose , Modi Shanu 
Published: May 2015

Abstract
Background: Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2+) are driven by HER2/HER3/PI3K signaling. Single agent therapy against this pathway is only modestly effective due to redundant mechanisms of pathway activation and regulatory feedback loops. Drug combinations designed to directly inhibit multiple nodes simultaneously have proven synergistic in preclinical models. Single agents and doublets targeting HER2, HER3, and PI3K have thus far proven safe in clinical testing. Methods: We are conducting a phase I clinical trial of LJM716, a fully human monoclonal antibody against HER3, plus BYL719, a small molecule alpha-specific PI3K inhibitor, and trastuzumab, an approved human monoclonal antibody against HER2, in patients (pts) with HER2+ metastatic breast cancer (MBC). There will be dose-escalation and dose-expansion phases, with correlative serum and tumor tissue studies. The primary objective is to determine the MTD of BYL719 with fixed dose LJM716 and trastuzumab in pts with HER2+, PIK3CA mutated MBC; determination of MTD will utilize the Continual Reassessment Method (CRM). LJM716 will be administered at 20mg/kg and trastuzumab at 2mg/kg, both intravenously weekly; starting dose of BYL719 will be 250mg orally daily, with dose escalation to MTD. Secondary objectives are to describe safety (CTCAE 4.0) and preliminary efficacy (RECIST v1.1) of the combination and to describe immunogenicity of LJM716. Exploratory objectives are to assess pre-treatment (tx) genomic alterations predictive of response or resistance to the tx; to assess proteomic pharmacodynamics markers of effective HER2, HER3 and PI3K inhibition, and to correlate cell-free DNA mutant allele fraction with clinical response. For these correlative studies, all pts will undergo serial plasma collection for cell-free DNA, and 10 pts will undergo pre-tx, on-tx, and at-progression biopsies. Eligible pts for dose-escalation and expansion are required to have ECOG 0-1, HER2+ MBC (immunohistochemistry 3+ or in-situ hybridization ≥ 2.0), and prior treatment with pertuzumab and ado-trastuzumab emtansine. For dose-escalation, pts may have measurable or non-measurable disease and somatic PIK3CA mutations are required. For dose-expansion, pts must have measurable disease and there will be two cohorts: one for wild-type and the other for mutant PIK3CA tumors. Accrual beginning June 2014 will include an anticipated 18 pts for dose-escalation and 30 pts for the expansion. Contact modis@mskcc.org for further information.
Citation Format: Payal D Shah, Sarat Chandarlapaty, Gary Ulaner, Stephen Zamora, Valentina Sterlin, Alexia Iasonos, Maura N Dickler, Mary Ellen Moynahan, Clifford A Hudis, Jose Baselga, Shanu Modi. Phase I, open-label study evaluating the safety and tolerability of LJM716, BYL719 and trastuzumab in patients with metastatic HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-05.