90TiP - A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC; +/- endocrine therapy), or non-small-cell lung cancer (NSCLC)

Abstract

Background: The insulin-like growth factor (IGF) and the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathways have been implicated in the pathogenesis and resistance mechanisms of various cancers, including HR+, HER2- BC and NSCLC. IGF ligand-dependent signaling via the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing a rationale for simultaneous inhibition of IGF and CDK4/6. This 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 inhibitor of CDK4 and 6, +/- endocrine therapy, in pts with solid tumors. Trial design: Study BI 1280.18 is a phase Ib multicenter, non-randomized, open-label, dose-escalation trial with four dose-finding cohorts (Cohorts A–D) and two expansion cohorts (Cohorts E, F). Pts must be aged ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤ 1, and unresectable advanced/metastatic solid tumors after failure on standard therapy (Cohort A), postmenopausal locally advanced/metastatic HR+, HER2- BC (Cohorts B–D, F), or stage IV NSCLC after 1–2 lines of therapy and failure after platinum-based chemotherapy and immunotherapy (Cohort E). CDK4/6 inhibitor-naïve pts (Cohorts A–E) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. Pts will receive either xentuzumab plus abemaciclib alone (Cohorts A, E) or in combination (at MTD defined in Cohort A) with letrozole (Cohort B), anastrozole (Cohort C), or fulvestrant (Cohorts D, F [at MTD for cohort D]). Primary endpoints are MTD and/or RP2D (Cohorts A–D) and objective response (Cohorts E, F). Further efficacy outcomes, pharmacokinetics, safety, and tolerability will also be assessed in all cohorts. This study will be conducted in the USA, Europe, and Japan. Pt screening started in May 2017. Target enrollment is ∼88 pts. Clinical trial indentification: NCT03099174; 1280.18. Legal entity responsible for the study: Boehringer Ingelheim Funding: Boehringer Ingelheim Disclosure: A. Prat: Advisory board for Nanostring Technologies. E.L. Johnston: Owns stocks in and is an employee of Eli Lilly and Company. T. Bogenrieder: Employee of Boehringer Ingelheim and has stocks in Roche, Seattle Genetics and Immunogen. P. LoRusso: Served on advisory boards for Alexion, Ariad, CytomX, GenMab, Glenmark, Halozyme, Ignyta, Menarini, Novartis, Omniox. She served on a data safety monitoring board for Agios. She also was a member of imCORE Alliance with Roche-Genetech. All other authors have declared no conflicts of interest.