title: Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET.
abstract: OBJECTIVE
  SGX523 is an orally bio-available, ATP competitive, small molecule inhibitor of MET, binding the kinase domain active site in a novel mode. Two phase 1, open-label, dose-escalation studies of SGX523 were conducted to evaluate both interrupted and continuous dosing schedules.
  
  
  METHODS
  Thirty-six patients per study were planned to be enrolled. The first study explored a 21-day cycle with SGX523 administered on an intermittent schedule at a starting dose of 60 mg PO BID for 14 days followed by 7 days of rest. The second protocol explored a continuous 28-day dosing schedule with SGX523 administered at a starting dose of 20 mg PO BID for 28 days without rest.
  
  
  RESULTS
  A total of 10 patients were enrolled, 2 on the intermittent dosing protocol and 8 on the continuous dosing protocol. All 6 patients that received daily doses of ≥ 80 mg developed unexpected renal failure manifested by an early rise of serum blood urea nitrogen and creatinine. Human PK analysis revealed the formation of two insoluble metabolites at levels not seen in the rat or dog preclinical toxicology studies. Subsequent primate toxicology and toxicokinetic evaluation replicated human findings, and histological examination of the monkey kidneys revealed the formation of crystals both within the renal tubules and within giant cell macrophages.
  
  
  CONCLUSIONS
  Two-species toxicology studies of SGX523 did not predict the occurrence of renal toxicity in the human. Subsequent primate toxicology studies suggest the cause of the renal failure seen in humans was a crystal nephropathy secondary to insoluble metabolites. SGX523 is no longer in clinical development.
authors.affiliation: Sarah Canon Research Institute, 250 25th Avenue, Suite 200, Nashville, TN 37203, USA. jinfante@tnonc.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Terence
authors.initials: T
authors.lastname: Rugg
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rooney
authors.forename: Lee
authors.initials: L
authors.lastname: Rosen
authors.forename: Karin
authors.initials: K
authors.lastname: Zeh
authors.forename: Raymond
authors.initials: R
authors.lastname: Liu
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000293:Adolescent; D000818:Animals; D004285:Dogs; D005500:Follow-Up Studies; D000882:Haplorhini; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000627:therapeutic use*; D051381:Rats; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000473:pathology*; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D011724:Pyridazines; D014230:Triazoles; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met