Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory Small Cell Lung Cancer.

Abstract

INTRODUCTION\nThis first-time-in-human study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed/refractory small cell lung carcinoma (SCLC).\n\n\nMETHODS\nThis Phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed/refractory SCLC (after ≥1 platinum-containing chemotherapy, or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary endpoint (Part 1) was to determine the safety, tolerability, and recommended dose/regimen of GSK2879552. Secondary endpoints were to characterize PK and PD parameters and measure disease control rate at Week 16. Part 2 was not conducted.\n\n\nRESULTS\nBetween 4 February 2014 and 18 April 2017, 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once-daily, and 3 mg or 4 mg intermittent dosing). Twenty-two patients completed the study; 7 withdrew, primarily due to adverse events (AEs). Most patients (24/29; 83%) had ≥1 treatment-related AE, most commonly thrombocytopenia (12/29; 41%). Twelve serious AEs (SAEs) were reported by 9 patients; 6 were considered treatment-related, the most common of which was encephalopathy (4 SAEs). Three patients died; one related to SAEs. PK was characterized by rapid absorption, slow elimination, and dose-proportional increase in exposure.\n\n\nCONCLUSIONS\nGSK2879552 is a potent, selective inhibitor of LSD1 and demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated as the risk-benefit profile did not favor continuation.