Abstract OT3-06-02: A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy)
Authors: Yee D , Sablin MP , Iwata H , Johnston EL , Bogenrieder T , Serra J , Hua H , Lo Russo P , Prat A 
Published: February 2018

Abstract
Background: Resistance to endocrine therapy remains an important clinical problem in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC), necessitating alternative treatment options. The insulin-like growth factor (IGF) axis and cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including BC. Binding of IGF-I and -II to the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing rationale for the simultaneous inhibition of IGF-I and -II and CDK4/6. This Phase Ib trial assesses the maximum-tolerated dose (MTD)/recommended phase II dose (RP2D), safety and preliminary efficacy of the IGF-ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective, small-molecule inhibitor of both CDK4 and 6, in patients (pts) with solid tumors. The trial includes four dose finding cohorts followed by two expansion cohorts. Only those cohorts that will include pts with postmenopausal HR+, HER2- BC will be presented here.
Trial design: In this phase Ib multicenter, non-randomized, open-label, dose escalation trial (BI 1280.18 [NCT03099174]), the key aims in the BC cohorts (Cohorts B–D, F) are to define the MTD or recommended phase 2 dose (RP2D), and to evaluate the preliminary efficacy, safety and tolerability of xentuzumab plus abemaciclib in combination with endocrine therapies. Eligible pts include adults ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤1, and postmenopausal locally advanced or metastatic HR+, HER2- BC (Cohorts B–D, F). CDK4/6 inhibitor-naïve pts (Cohorts B–D) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. The MTD/RP2D of xentuzumab plus abemaciclib to be used in Cohorts B–D will be established in pts with solid tumors (Cohort A) who will receive xentuzumab (starting dose 1000mg weekly iv) plus abemaciclib (starting dose 150mg every 12 hours). CDK4/6 inhibitor-naïve pts with BC will receive xentuzumab plus abemaciclib at the RP2D determined in Cohort A in combination with letrozole (2.5mg/day; Cohort B), anastrozole (1mg/day; Cohort C), or fulvestrant (500mg/month; Cohort D). CDK4/6 inhibitor pre-treated pts with BC (Cohort F) will receive xentuzumab plus abemaciclib and fulvestrant at the RP2D determined in Cohort D. Primary endpoints in the BC cohorts are the MTD and/or RP2D of xentuzumab plus abemaciclib in combination with endocrine therapies, and the objective response (OR) in CDK4/6 inhibitor pre-treated pts with advanced BC (Cohort F); disease control (DC), duration of DC, time to OR, duration of OR, and progression-free survival (PFS) in Cohort F are secondary endpoints. Additionally, PK outcomes, safety and tolerability will be assessed in all cohorts. This study will be conducted in the US, Europe and Japan. Pt screening started in May 2017. Target enrolment is ˜88 pts, including ˜56 pts with advanced HR+, HER2- BC, of whom ˜20 had previously been treated with CDK 4/6 inhibitors.
Citation Format: Yee D, Sablin MP, Iwata H, Johnston EL, Bogenrieder T, Serra J, Hua H, Lo Russo P, Prat A. A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-02.