Abstract
Purpose 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). Conclusion 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.
Original language | English (US) |
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Pages (from-to) | 1591-1596 |
Number of pages | 6 |
Journal | Investigational New Drugs |
Volume | 30 |
Issue number | 4 |
DOIs | |
State | Published - Aug 2012 |
Keywords
- PX-12
- Phase I study
- Solid tumors
- Thioredoxin
ASJC Scopus subject areas
- Oncology
- Pharmacology
- Pharmacology (medical)