Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies

Timothy A Yap, David Olmos, Andre T Brunetto, Nina Tunariu, Jorge Barriuso, Ruth Riisnaes, Lorna Pope, Jeremy Clark, Andrew Futreal, Michael Germuska, David Collins, Nandita M deSouza, Martin O Leach, Ronald E Savage, Carol Waghorne, Feng Chai, Edward Garmey, Brian Schwartz, Stan B Kaye, Johann S de Bono

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis.

PATIENTS AND METHODS: Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled.

RESULTS: Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers.

CONCLUSION: ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.

Original languageEnglish
Pages (from-to)1271-1279
Number of pages9
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume29
Issue number10
DOIs
Publication statusPublished - 1 Apr 2011

Keywords

  • Adolescent
  • Adult
  • Aged
  • Angiogenesis Inhibitors/adverse effects
  • Apoptosis/drug effects
  • Aryl Hydrocarbon Hydroxylases/genetics
  • Biopsy
  • Cytochrome P-450 CYP2C19
  • Endothelial Cells/drug effects
  • England
  • Female
  • Focal Adhesion Kinase 1/metabolism
  • Humans
  • In Situ Nick-End Labeling
  • Magnetic Resonance Imaging
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms/blood supply
  • Neoplastic Cells, Circulating/drug effects
  • Neovascularization, Pathologic/prevention & control
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors/adverse effects
  • Proto-Oncogene Proteins c-met/antagonists & inhibitors
  • Pyrrolidinones/adverse effects
  • Quinolines/adverse effects
  • Receptors, Growth Factor/antagonists & inhibitors
  • Signal Transduction/drug effects
  • Treatment Outcome
  • Young Adult

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

Fingerprint

Dive into the research topics of 'Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies'. Together they form a unique fingerprint.

Cite this