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

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

Research output: Contribution to journalArticle

20 Scopus citations

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 languageEnglish (US)
Pages (from-to)1591-1596
Number of pages6
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
StatePublished - Aug 1 2012

Keywords

  • PX-12
  • Phase I study
  • Solid tumors
  • Thioredoxin

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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