title: Phase I trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies.
abstract: BACKGROUND
  Heat shock protein (HSP)90 regulates the function of proteins responsible for cell growth and survival, is overexpressed in many cancers and is an attractive therapeutic target. We undertook a phase 1 trial of PF-04929113 (SNX-5422), a novel oral HSP90 inhibitor, to estimate the maximum tolerated dose and describe the pharmacokinetic and toxicity profiles.
  
  
  METHODS
  Patients with relapsed, refractory, hematologic malignancies and adequate organ function were eligible. PF-04929113 was administered orally every other day for 21 days of a 28-day cycle. Twenty-five patients were treated, with dose escalation ranging from 5.32 mg/m(2) to 74 mg/m(2) using a 3 plus 3 trial design.
  
  
  RESULTS
  All 25 patients enrolled were evaluable for toxicity. Most common toxicities included prolonged QTc interval, diarrhea, pruritus, thrombocytopenia, fatigue, and nausea. Grade 3/4 treatment-related adverse events were experienced by 7/25 patients (28%); thrombocytopenia was the most common (n = 3 grade 3; n = 2 grade 4). Partial response was experienced by a patient with transformed lymphoma, and prolonged stabilization of disease was observed in a patient with multiple myeloma.
  
  
  CONCLUSIONS
  Alternate-day oral dosing of PF-04929113 at 74 mg/m(2) for 21/28 days was generally well tolerated with reversible toxicity. The responses observed in myeloma and lymphoma patients are encouraging.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Nishitha.reddy@vanderbilt.edu
authors.forename: Nishitha
authors.initials: N
authors.lastname: Reddy
authors.forename: Peter M
authors.initials: PM
authors.lastname: Voorhees
authors.forename: Brett E
authors.initials: BE
authors.lastname: Houk
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Brega
authors.forename: James M
authors.initials: JM
authors.lastname: Hinson
authors.forename: Anand
authors.initials: A
authors.lastname: Jillela
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D055815:Young Adult
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; C561943:SNX-5422; D005998:Glycine
keywords: Clinical trial; Heat shock protein; Pharmacokinetics