title: An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer.
abstract: BACKGROUND
  This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors.
  
  
  METHODS
  Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m(2)). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated.
  
  
  RESULTS
  CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m(2). The MTD of CEP-11981 was determined to be 97.4 mg/m(2), with DLTs observed at the 126.6 mg/m(2) dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m(2) and 1 patient at 126.6 mg/m(2)), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44% patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m(2).
  
  
  CONCLUSIONS
  In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
authors.affiliation: Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA, Roberto.Pili@RoswellPark.org.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Peter
authors.initials: P
authors.lastname: Brown
authors.forename: Herbert
authors.initials: H
authors.lastname: Hurwitz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002227:Carbazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D066066:Response Evaluation Criteria in Solid Tumors; D013552:Swine; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C571190:11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo(5,4-a)pyrrolo(3,4-c)carbazol-4-one; D000970:Antineoplastic Agents; D002227:Carbazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2