Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
| العنوان: | Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors |
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| المؤلفون: | 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 |
| المصدر: | JCI Insight, Vol 3, Iss 4 (2018) JCI insight, vol 3, iss 4 |
| بيانات النشر: | American Society for Clinical investigation, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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). |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2379-3708 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f1125084220541ce8d767feec5c05a4Test https://doaj.org/article/675b9e9f9e9e4e0f87e9c28de4f3db4bTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0f1125084220541ce8d767feec5c05a4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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