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

Abstract

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).

• Authors: Stergios J Moschos, Ryan J Sullivan, Wen-Jen Hwu, Ramesh K Ramanathan, Alex A Adjei, Peter C Fong, Ronnie Shapira-Frommer, Hussein A Tawbi, Joseph Rubino, Thomas S Rush 3rd, Da Zhang, Nathan R Miselis, Ahmed A Samatar, Patrick Chun, Eric H Rubin, James Schiller, Brian J Long, Priya Dayananth, Donna Carr, Paul Kirschmeier, W Robert Bishop, Yongqi Deng, Alan Cooper, Gerald W Shipps, Blanca Homet Moreno, Lidia Robert, Antoni Ribas, Keith T Flaherty
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 4 (02 22 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 29467321 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• MK-8353
• Protein Kinase Inhibitors
• Pyridines
• Pyrrolidines
• Triazoles
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Administration, Oral
• Adult
• Animals
• Biological Availability
• Cell Line, Tumor
• Diarrhea (chemically induced, epidemiology)
• Dogs
• Dose-Response Relationship, Drug
• Drug Eruptions (epidemiology, etiology)
• Drug Evaluation, Preclinical
• Fatigue (chemically induced, epidemiology)
• Female
• Humans
• Indazoles (pharmacology, therapeutic use)
• MAP Kinase Signaling System (drug effects)
• Male
• Maximum Tolerated Dose
• Mice
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Nausea (chemically induced, epidemiology)
• Neoplasm Staging
• Neoplasms (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Pyrrolidines (pharmacology, therapeutic use)
• Rats
• Triazoles (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• Young Adult