title: Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours.
abstract: BACKGROUND
  Orally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422.
  
  
  METHODS
  Using a dose-escalation design, 3-6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined.
  
  
  RESULTS
  In total, 56 patients were enrolled: QOD 3 weeks on/1 week off, n=36; QD 3weeks on/1 week off, n=17; QD continuous, n=3. Doses ranged from 4 to 133mg/m(2) QOD and 50 to 89 mg/m(2) QD. The MTDs were defined as 100mg/m(2) QOD and 67 mg/m(2) QD, respectively, with diarrhoea being dose-limiting on both 3 weeks on/1 week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1-3 nyctalopia (night blindness) was reported by four patients (dose: 50-89mg/m(2) QD; 100mg/m(2) QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2+breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾ 6 months.
  
  
  CONCLUSIONS
  The dose and schedule recommended for further study with SNX-5422 is 100mg/m(2) QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA. Electronic address: jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Unicorn Pharma Consulting, Brentwood, TN, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Hinson
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Esanex Inc, Indianapolis, IN, USA.
authors.forename: Everardus O
authors.initials: EO
authors.lastname: Orlemans
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005998:Glycine; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs; D014786:Vision Disorders / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007191:Indazoles; D011355:Prodrugs; C534922:SNX 2112; C561943:SNX-5422; D005998:Glycine
keywords: Heat shock protein 90 inhibitor; Phase I; SNX-2112; SNX-5422; Solid tumours