title: First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, UK.
authors: Timothy A
authors: TA
authors: Yap
authors: Hendrik-Tobias
authors: HT
authors: Arkenau
authors: D Ross
authors: DR
authors: Camidge
authors: Suzanne
authors: S
authors: George
authors: Natalie J
authors: NJ
authors: Serkova
authors: Stephen J
authors: SJ
authors: Gwyther
authors: Jennifer L
authors: JL
authors: Spratlin
authors: Rohit
authors: R
authors: Lal
authors: James
authors: J
authors: Spicer
authors: Nandita M
authors: NM
authors: Desouza
authors: Martin O
authors: MO
authors: Leach
authors: Jon
authors: J
authors: Chick
authors: Srinivasu
authors: S
authors: Poondru
authors: Ramesh
authors: R
authors: Boinpally
authors: Richard
authors: R
authors: Gedrich
authors: Katie
authors: K
authors: Brock
authors: Andrew
authors: A
authors: Stephens
authors: S Gail
authors: SG
authors: Eckhardt
authors: Stan B
authors: SB
authors: Kaye
authors: George
authors: G
authors: Demetri
authors: Michelle
authors: M
authors: Scurr
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism
chemical_list: C505207:OSI 930; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2
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