A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers.
We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m(2) /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non-bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF-2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies.
A F
AF
Baker
K N
KN
Adab
N
N
Raghunand
Hhs
H
Chow
S P
SP
Stratton
S W
SW
Squire
M
M
Boice
L A
LA
Pestano
D L
DL
Kirkpatrick
T
T
Dragovich
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004220:Disulfides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011859:Radiography; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D000970:Antineoplastic Agents; D004220:Disulfides; D007093:Imidazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide