Erschienen in:
01.08.2012 | PHASE I STUDIES
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
verfasst von:
Ramesh K. Ramanathan, Joe J. Stephenson, Glen J. Weiss, Linda A. Pestano, Ann Lowe, Alton Hiscox, Rafael A. Leos, Julie C. Martin, Lynn Kirkpatrick, Donald A. Richards
Erschienen in:
Investigational New Drugs
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Ausgabe 4/2012
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Summary
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/m2/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/m2 (n = 3), 400 mg/m2 (n = 10) and 500 mg/m2 (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/m2 and grade 3 reversible pneumonitis at the 500 mg/m2 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/m2/day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.