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 a variety of cancers, including HR+ HER2- BC and NSCLC. IGF-ligand dependent signalling via the IGF receptor results in upregulation of cyclin D1, and thus, progression through the cell cycle, providing rationale for the simultaneous inhibition of IGF and CDK4/6. This trial assesses the maximum-tolerated dose (MTD), safety and preliminary efficacy of the IGF ligand-neutralising antibody, xentuzumab, in combination with abemaciclib, a selective inhibitor of both CDK4 and 6, +/- hormone therapy, in pts with solid tumours.
Study BI 1280.18 (NCT03099174) is a Phase Ib multicentre, non-randomised, open-label, dose escalation trial with four dose-finding cohorts (Cohorts A–D) followed by two expansion cohorts (Cohorts E, F). Eligible pts include adults ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤ 1, and unresectable advanced or metastatic solid tumours after failure on standard therapy (Cohort A), postmenopausal locally advanced or metastatic HR+, HER2- BC (Cohorts B–D, F), or stage IV NSCLC after 1–2 lines of therapy and failure after platinum-based chemotherapy (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 for the doublet therapy) with letrozole (Cohort B), anastrozole (Cohort C), or fulvestrant (Cohorts D, F). Primary endpoints are the MTD and/or recommended phase-2-dose (RP2D; Cohorts A–D), and objective response (Cohorts E, F). Further endpoints include antitumour activity (Cohorts E, F), and pharmacokinetic outcomes (all Cohorts). This study will be conducted in the US, Europe and Japan. Pt screening is planned to start May 17; target enrolment: N≈88.
Clinical trial identification
Legal entity responsible for the study
P. Lo Russo: Advisory boards: Agios: Data Safety Monitoring Board (2016-2017), Alexion: Advisory Board Member (2016-2017), Ariad: Advisory Board Member (2016-2017), GenMab: Advisory Board Member (2016-2017), Glenmark: Advisory Board Member (2016-2017), Halozyme: Data Safety Monitoring Board (2016-2017), Menarini: Advisory Board Member (2016-2017), Novartis: Advisory Board Member (2016-2017), Roche-Genentech: imCORE Alliance (2016-2019), Genentech: Advisory Board (2016-2017), CytomX: Advisory Board Member (2016-2017), Omniox: Advisory Board Member (2016-2017), Ignyta: Advisory Board Member (2016-2017). M.P. Sablin: Advisory board: Boehringer Ingelheim. E.L. Johnston: Employment: Eli Lilly and Company. Stock ownership or options: Eli Lilly and Company. T. Bogenrieder, J. Serra, K. Stucke-Straub: Employee of BI. All other authors have declared no conflicts of interest.