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

Autor: Thomas S. Rush, Hussein Tawbi, Yongqi Deng, Wen-Jen Hwu, Paul Kirschmeier, Ryan J. Sullivan, Joseph Rubino, Ahmed A. Samatar, Lidia Robert, Gerald W. Shipps, Keith T. Flaherty, Donna Carr, Peter C.C. Fong, Antoni Ribas, Patrick Chun, Brian Long, Eric H. Rubin, Priya Dayananth, Ramesh K. Ramanathan, Ronnie Shapira-Frommer, Stergios J. Moschos, Blanca Homet Moreno, W. Robert Bishop, Alan B. Cooper, James E. Schiller, Alex A. Adjei, Nathan R. Miselis, Da Zhang
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Pyrrolidines
Pyridines
Drug Evaluation
Preclinical
Administration
Oral
Phases of clinical research
lcsh:Medicine
Pharmacology
Signal transduction
Mice
0302 clinical medicine
Clinical trials
Neoplasms
Medicine
Melanoma
Fatigue
Cancer
Mitogen-Activated Protein Kinase 1
Tumor
Mitogen-Activated Protein Kinase 3
Nausea
General Medicine
Middle Aged
Preclinical
Tolerability
Oncology
030220 oncology & carcinogenesis
6.1 Pharmaceuticals
Toxicity
Administration
Female
Drug Eruptions
Drug
Diarrhea
Oral
Adult
Indazoles
Maximum Tolerated Dose
MAP Kinase Signaling System
Clinical Trials and Supportive Activities
Biological Availability
Cell Line
Dose-Response Relationship
03 medical and health sciences
Young Adult
Dogs
Pharmacokinetics
Clinical Research
Cell Line
Tumor
Animals
Humans
Clinical Trials
Adverse effect
Protein Kinase Inhibitors
Neoplasm Staging
Dose-Response Relationship
Drug
business.industry
lcsh:R
Evaluation of treatments and therapeutic interventions
Triazoles
medicine.disease
Xenograft Model Antitumor Assays
Rats
Clinical trial
030104 developmental biology
Pharmacodynamics
Drug Evaluation
Clinical Medicine
business
Zdroj: JCI Insight, Vol 3, Iss 4 (2018)
JCI insight, vol 3, iss 4
ISSN: 2379-3708
Popis: 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: OpenAIRE
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