title: A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial ( clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed.
  
  
  METHODS
  Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated.
  
  
  RESULTS
  No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2-[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29.
  
  
  CONCLUSIONS
  Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.
authors.affiliation: Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA.
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Gil
authors.initials: G
authors.lastname: Fine
authors.forename: Gavin
authors.initials: G
authors.lastname: Choy
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Redkar
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.forename: Aram
authors.initials: A
authors.lastname: Oganesian
authors.forename: Amarpal
authors.initials: A
authors.lastname: Sahai
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azab
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013890:Thiourea
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019009:Proto-Oncogene Proteins c-kit; D013890:Thiourea; C521047:amuvatinib