First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: Results of a phase I dose-escalation and expansion study Journal Article
| Authors: | Sullivan, R. J.; Infante, J. R.; Janku, F.; Lee Wong, D. J.; Sosman, J. A.; Keedy, V.; Patel, M. R.; Shapiro, G. I.; Mier, J. W.; Tolcher, A. W.; Wang-Gillam, A.; Sznol, M.; Flaherty, K.; Buchbinder, E.; Carvajal, R. D.; Varghese, A. M.; Lacouture, M. E.; Ribas, A.; Patel, S. P.; DeCrescenzo, G. A.; Emery, C. M.; Groover, A. L.; Saha, S.; Varterasian, M.; Welsch, D. J.; Hyman, D. M.; Li, B. T. |
| Article Title: | First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: Results of a phase I dose-escalation and expansion study |
| Abstract: | Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatmentrelated adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF -mutant solid tumors. Significance: Here, we describe the fi rst-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profi le with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS - and BRAF V600-and non-V600 mutant solid-tumor malignancies. © 2017 American Association for Cancer Research. |
| Keywords: | adult; controlled study; treatment response; aged; fatigue; diarrhea; genetic analysis; melanoma; anemia; mitogen activated protein kinase inhibitor; nausea; randomized controlled trial; vomiting; dehydration; cohort analysis; risk assessment; drug dose escalation; pruritus; rash; body mass; karnofsky performance status; immunotherapy; multicenter study; peripheral edema; open study; eye disease; phase 1 clinical trial; alopecia; lactate dehydrogenase blood level; decreased appetite; mapk signaling; very elderly; human; male; female; article; x-ray computed tomography; solid malignant neoplasm; ulixertinib |
| Journal Title: | Cancer Discovery |
| Volume: | 8 |
| Issue: | 2 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-02-01 |
| Start Page: | 184 |
| End Page: | 195 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-17-1119 |
| PROVIDER: | scopus |
| PUBMED: | 29247021 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
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