title: A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination.
abstract: OBJECTIVE
  This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).
  
  
  METHODS
  PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued.
  
  
  RESULTS
  Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively.
  
  
  CONCLUSIONS
  Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.
authors.affiliation: Virgina G Piper Cancer Center, TGen, Scottsdale, AZ, 85259, USA. rramanathan@tgen.org
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: James
authors.initials: J
authors.lastname: Abbruzzese
authors.forename: Tomislav
authors.initials: T
authors.lastname: Dragovich
authors.forename: Lynn
authors.initials: L
authors.lastname: Kirkpatrick
authors.forename: Jose M
authors.initials: JM
authors.lastname: Guillen
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
authors.forename: Linda A
authors.initials: LA
authors.lastname: Pestano
authors.forename: Sylvan
authors.initials: S
authors.lastname: Green
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004220:Disulfides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D000090063:Proto-Oncogene Mas; D013534:Survival; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000097:blood; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D007093:Imidazoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C491203:TXN protein, human; D003841:Deoxycytidine; D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide; D000093542:Gemcitabine