A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors Journal Article
| Authors: | Schram, A. M.; Boni, V.; Adjei, A. A.; Olszanski, A. J.; Vieito, M.; Francis, J. H.; Kurman, M.; Ahsan, J. M.; Tomkinson, B.; Garralda, E. |
| Article Title: | A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors |
| Abstract: | 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. © 2025 Kura Oncology, Inc., The Author(s) |
| Keywords: | signal transduction; adult; middle aged; unclassified drug; gene mutation; major clinical study; drug tolerability; fatigue; cancer recurrence; advanced cancer; area under the curve; drug safety; drug withdrawal; monotherapy; side effect; solid tumor; treatment duration; pancreas cancer; antineoplastic agent; colorectal cancer; melanoma; progression free survival; computer assisted tomography; ovary cancer; pharmacodynamics; anemia; mitogen activated protein kinase inhibitor; nausea; vomiting; qt prolongation; cohort analysis; lung cancer; antineoplastic activity; continuous infusion; oncogene h ras; asthenia; drug dose escalation; dyspnea; lymphocytopenia; rash; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; hypokalemia; head and neck cancer; multicenter study; uterine cervix cancer; drug clearance; single drug dose; retina detachment; open study; diastolic blood pressure; systolic blood pressure; bile duct carcinoma; intravenous administration; dermatitis; headache; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; gamma glutamyltransferase; k ras protein; esophagus cancer; dyspepsia; b raf kinase; adverse drug reaction; treatment withdrawal; respiratory tract infection; solid tumors; blurred vision; phase i; pharmacokinetic parameters; oncogene n ras; gastroesophageal junction cancer; subretinal fluid; demographics; macular edema; response evaluation criteria in solid tumors; Common Terminology Criteria for Adverse Events; photopsia; infusion related reaction; human; male; female; article; volume of distribution; ecog performance status; maximum concentration; retina edema; dermatitis acneiform; vitreous body detachment; erk1/2 inhibition; ko-947; ko 947 |
| Journal Title: | ESMO Open |
| Volume: | 10 |
| Issue: | 3 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2025-03-01 |
| Start Page: | 104300 |
| Language: | English |
| DOI: | 10.1016/j.esmoop.2025.104300 |
| PROVIDER: | scopus |
| PMCID: | PMC11904481 |
| PUBMED: | 39985888 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alison Schram -- Source: Scopus |
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