First-In-Human Phase I Study of a Next-Generation, Oral, Transforming Growth Factor-Beta Receptor 1 Inhibitor, LY3200882 in Patients with Advanced Cancer.

Abstract

PURPOSE\nA novel, selective, next-generation transforming growth factor-beta receptor type 1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.\n\n\nEXPERIMENTAL DESIGN\nThis phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (PC; LY3200882, gemcitabine and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin and radiation).\n\n\nRESULTS\nOverall, 139 patients with advanced cancer were treated. Majority (93.5%) of patients experienced {greater than or equal to}1 treatment-emergent adverse events (TEAEs), with 39.6% LY3200882-related Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the PC arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in 2 schedules: 50 mg BID 2-weeks-on/2-weeks-off and 35 mg BID 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable RANO partial responses (PR) with LY3200882 monotherapy (n=3) or LY3200882-LY3300054 combination therapy (n=1). In treatment-naive patients with advanced PC, 6/12 patients achieved RECIST v1.1 PR and 3/12 patients demonstrated stable disease, for an overall 75% disease control rate with the combination of LY3200882, gemcitabine and nab-paclitaxel.\n\n\nCONCLUSIONS\nLY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in PC. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced PC are warranted.