title: Inappropriate dose of multitargeted tyrosine kinase inhibitors: the original sin.
abstract: The use of antiangiogenic tyrosine kinase inhibitors (TKIs) is challenging and often requires dose adaptation and transient or definitive treatment interruption. We believe that the inappropriate recommended dose of TKI is related to no optimal study designs in the early development of the drug.
  
  
  
  As an example of this, we described herein some pitfalls made in the successive development of sunitinib, sorafenib, regorafenib, and pazopanib, but there are several other examples of early drugs development illustrating this issue.
  
  
  
  Regarding the antiangiogenic TKI mechanism of action, we strongly feel that innovative approaches are needed such as extended dose-limiting toxicity period or a better definition of the induced toxicity. Furthermore, before classic phase II/III trials, an intermediate step may be needed to better define the recommended phase II dose, such as a randomized phase I/II trial with several expansion cohorts.
authors.affiliation: Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
authors.forename: Nuria
authors.initials: N
authors.lastname: Kotecki
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases