A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors

Background: KO-947, a potent, intravenously administered, extracellular signal-regulated kinase (ERK) inhibitor, has demonstrated activity in preclinical models. This phase I trial of KO-947 evaluated maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with relapsed/refractory solid tumors. Materials and methods: This multicenter, open-label, dose-escalation study evaluated KO-947 0.45-11.3 mg/kg in three schedules. Schedules 1 (0.45-5.4 mg/kg, 1- to 2-hour infusion) and 2 (4.8-9.6 mg/kg, 4-hour infusion) were administered once weekly on a 28-day cycle. Schedule 3 (3.6-11.3 mg/kg, 4-hour infusion) was administered on days 1, 4, and 8 (and on days 11 and 15 for two patients) on a 21-day cycle. The primary objective was determination of MTD and/or recommended phase II dose. Safety analysis included adverse events of special interest (AESIs), namely ocular toxicities and infusion-related reactions (e.g. hypotension, corrected QT interval prolongation). Results from the dose-escalation portion of the phase I study are presented due to trial termination before preplanned cohort expansion cohorts. Results: All 61 enrolled patients (schedules 1/2, n = 34, schedule 3, n = 27) discontinued treatment, mostly owing to disease progression (88% and 67%). The MTD for schedule 1 was 3.6 mg/kg; the maximum administered doses for schedules 2 and 3 were 9.6 and 11.3 mg/kg, respectively. Treatment-related adverse events occurred in 88% of patients in schedules 1/2, and 92% in schedule 3; most common were blurred vision (schedules 1/2, 50.0%; schedule 3, 33.3%). AESIs occurred in 50% of patients in schedules 1/2, and 82% in schedule 3. In all schedules, the best overall response was stable disease. Conclusions: Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors.