Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors.

Autor:	Moschos SJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Sullivan RJ; Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA., Hwu WJ; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Ramanathan RK; Translational Genomics Research Institute, Phoenix, Arizona, USA; Virginia G. Piper Cancer Center, Scottsdale, Arizona, USA., Adjei AA; Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA., Fong PC; The University of Auckland and Auckland City Hospital, Auckland, New Zealand., Shapira-Frommer R; Department of International Medicine, Chaim Sheba Medical Center, Tel-HaShomer, Israel., Tawbi HA; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA., Rubino J; Merck & Co. Inc., Kenilworth, New Jersey, USA., Rush TS 3rd; Merck & Co. Inc., Kenilworth, New Jersey, USA., Zhang D; Merck & Co. Inc., Kenilworth, New Jersey, USA., Miselis NR; Merck & Co. Inc., Kenilworth, New Jersey, USA., Samatar AA; Merck & Co. Inc., Kenilworth, New Jersey, USA., Chun P; Merck & Co. Inc., Kenilworth, New Jersey, USA., Rubin EH; Merck & Co. Inc., Kenilworth, New Jersey, USA., Schiller J; Merck & Co. Inc., Kenilworth, New Jersey, USA., Long BJ; Merck & Co. Inc., Kenilworth, New Jersey, USA., Dayananth P; Merck & Co. Inc., Kenilworth, New Jersey, USA., Carr D; Merck & Co. Inc., Kenilworth, New Jersey, USA., Kirschmeier P; Merck & Co. Inc., Kenilworth, New Jersey, USA., Bishop WR; Merck & Co. Inc., Kenilworth, New Jersey, USA., Deng Y; Merck & Co. Inc., Kenilworth, New Jersey, USA., Cooper A; Merck & Co. Inc., Kenilworth, New Jersey, USA., Shipps GW; Merck & Co. Inc., Kenilworth, New Jersey, USA., Moreno BH; Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA., Robert L; Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA., Ribas A; Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA., Flaherty KT; Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2018 Feb 22; Vol. 3 (4). Date of Electronic Publication: 2018 Feb 22 (Print Publication: 2018).
DOI:	10.1172/jci.insight.92352
Abstrakt:	Background: Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. Methods: We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. Results: MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. Conclusion: MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. Trial Registration: ClinicalTrials.gov NCT01358331. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).
Databáze:	MEDLINE
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