First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies

Clin Cancer Res. 2013 Feb 15;19(4):909-19. doi: 10.1158/1078-0432.CCR-12-2258. Epub 2013 Feb 12.

Abstract

Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors.

Experimental design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted.

Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients.

Conclusions: OSI-930 is safe and well tolerated, with pharmacokinetic-pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Fatigue / chemically induced
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics
  • Thiophenes / administration & dosage*
  • Thiophenes / adverse effects
  • Thiophenes / pharmacokinetics
  • Vascular Endothelial Growth Factor Receptor-2 / drug effects
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • OSI 930
  • Protein Kinase Inhibitors
  • Quinolines
  • Thiophenes
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2