{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Schram AM"],"funding":["NCI NIH HHS"],"pagination":["104300"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11904481"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(3)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Materials and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors."],"journal":["ESMO open"],"pubmed_title":["A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors."],"pmcid":["PMC11904481"],"funding_grant_id":["P30 CA008748"],"pubmed_authors":["Francis JH","Boni V","Olszanski AJ","Ahsan JM","Vieito M","Kurman M","Garralda E","Adjei AA","Tomkinson B","Schram AM"],"additional_accession":[]},"is_claimable":false,"name":"A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors.","description":"<h4>Background</h4>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.<h4>Materials and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Mar","modification":"2026-06-01T06:04:45.246Z","creation":"2025-04-03T23:26:20.588Z"},"accession":"S-EPMC11904481","cross_references":{"pubmed":["39985888"],"doi":["10.1016/j.esmoop.2025.104300"]}}