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.

Autor: Ramanathan RK; Virginia G Piper Cancer Center/TGen, Scottsdale, AZ, USA. rramanathan@tgen.org, Stephenson JJ, Weiss GJ, Pestano LA, Lowe A, Hiscox A, Leos RA, Martin JC, Kirkpatrick L, Richards DA
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2012 Aug; Vol. 30 (4), pp. 1591-6. Date of Electronic Publication: 2011 Aug 24.
DOI: 10.1007/s10637-011-9739-9
Abstrakt: 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.
Databáze: MEDLINE
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