title: A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas.
  
  
  METHODS
  This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response.
  
  
  RESULTS
  Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m(2) administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction.
  
  
  CONCLUSIONS
  PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.
authors: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Arun
authors: A
authors: Rajan
authors: Ronan J
authors: RJ
authors: Kelly
authors: Jane B
authors: JB
authors: Trepel
authors: Yeong Sang
authors: YS
authors: Kim
authors: Sylvia V
authors: SV
authors: Alarcon
authors: Shivaani
authors: S
authors: Kummar
authors: Martin
authors: M
authors: Gutierrez
authors: Sonja
authors: S
authors: Crandon
authors: Wadih M
authors: WM
authors: Zein
authors: Lokesh
authors: L
authors: Jain
authors: Baskar
authors: B
authors: Mannargudi
authors: William D
authors: WD
authors: Figg
authors: Brett E
authors: BE
authors: Houk
authors: Michael
authors: M
authors: Shnaidman
authors: Nicoletta
authors: N
authors: Brega
authors: Giuseppe
authors: G
authors: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005998:Glycine; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; C561943:SNX-5422; D005998:Glycine