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

JCI Insight. 2018 Feb 22;3(4):e92352. doi: 10.1172/jci.insight.92352.

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).

Keywords: Cancer; Clinical Trials; Melanoma; Oncology; Signal transduction.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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

Associated data

  • ClinicalTrials.gov/NCT01358331