title: A phase I trial of PX-12, a small-molecule inhibitor of thioredoxin-1, administered as a 72-hour infusion every 21 days in patients with advanced cancers refractory to standard therapy.
abstract: OBJECTIVE
  This phase I trial assessed the safety, dose limiting toxicity (DLT) and pharmacodynamics of PX-12 in adult patients with advanced refractory cancers.
  
  
  METHODS
  PX-12 was administered to sequential cohorts as a 72-h infusion utilizing a portable infusion pump on days 1, 2, and 3 of a 21-day cycle at a starting dose level of 300 mg/m(2)/day and escalating dose levels till DLT was observed. Plasma thioredoxin (Trx-1), vascular endothelial growth factor (VEGF) and FGF-2 (fibroblast growth factor) levels were measured predose and during infusion of PX-12.
  
  
  RESULTS
  Patients (n = 14) were enrolled to the following dose cohorts, 300 mg/m(2) (n = 3), 400 mg/m(2) (n = 10) and 500 mg/m(2) (n = 1). Common grade 1/2 toxicities included fatigue, taste alteration and odor caused by expired drug metabolite. DLTs were one episode each of grade 3 hypoxia at the 400 mg/m(2) and grade 3 reversible pneumonitis at the 500 mg/m(2) dose levels. Best response was stable disease in a patient with rectal cancer. Predose Trx-1 levels (n = 12) ranged from 5.1 to 30.0 ng/mL (median 12.6 ng/mL).
  
  
  CONCLUSIONS
  PX-12 administered at 400 mg/m(2)/day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.
authors.affiliation: Virginia G Piper Cancer Center/TGen, Scottsdale, AZ, USA. rramanathan@tgen.org
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Joe J
authors.initials: JJ
authors.lastname: Stephenson
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Linda A
authors.initials: LA
authors.lastname: Pestano
authors.forename: Ann
authors.initials: A
authors.lastname: Lowe
authors.forename: Alton
authors.initials: A
authors.lastname: Hiscox
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Leos
authors.forename: Julie C
authors.initials: JC
authors.lastname: Martin
authors.forename: Lynn
authors.initials: L
authors.lastname: Kirkpatrick
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D004220:Disulfides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004220:Disulfides; D007093:Imidazoles; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide