title: A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors.
abstract: OBJECTIVE
  Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.
  
  
  METHODS
  Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).
  
  
  RESULTS
  Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).
  
  
  CONCLUSIONS
  Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors.
authors.affiliation: Tumour Biology Center, University Hospital, Freiburg, Germany. mross@tumorbio.uni-freiburg.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.forename: Annette
authors.initials: A
authors.lastname: Frost
authors.forename: Simone
authors.initials: S
authors.lastname: Steinbild
authors.forename: Susanne
authors.initials: S
authors.lastname: Hedbom
authors.forename: Martin
authors.initials: M
authors.lastname: Büchert
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fasol
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
authors.forename: Jörn
authors.initials: J
authors.lastname: Krätzschmar
authors.forename: Roland
authors.initials: R
authors.lastname: Heinig
authors.forename: Oliver
authors.initials: O
authors.lastname: Boix
authors.forename: Olaf
authors.initials: O
authors.lastname: Christensen
mesh_terms: D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000737:chemistry*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D042501:Angiogenic Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D011494:Protein Kinases; D019009:Proto-Oncogene Proteins c-kit; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human