A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors

Ramesh K. Ramanathan, D. Lynn Kirkpatrick, Chandra P. Belani, David Friedland, Sylvan B. Green, Hsiao-Hui Chow, Catherine A. Cordova, Steven P Stratton, Elizabeth R. Shadow, Amanda F Baker, Tomislav Dragovich

Research output: Contribution to journalArticle

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Abstract

Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1. Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks. Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the Cmax of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner. Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m 2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.

Original languageEnglish (US)
Pages (from-to)2109-2114
Number of pages6
JournalClinical Cancer Research
Volume13
Issue number7
DOIs
StatePublished - Apr 1 2007

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Thioredoxins
Pharmacokinetics
Neoplasms
Pneumonia
Appointments and Schedules
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Oxidation-Reduction
Research Design
Up-Regulation
Clinical Trials
Apoptosis
Safety
Growth
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. / Ramanathan, Ramesh K.; Kirkpatrick, D. Lynn; Belani, Chandra P.; Friedland, David; Green, Sylvan B.; Chow, Hsiao-Hui; Cordova, Catherine A.; Stratton, Steven P; Shadow, Elizabeth R.; Baker, Amanda F; Dragovich, Tomislav.

In: Clinical Cancer Research, Vol. 13, No. 7, 01.04.2007, p. 2109-2114.

Research output: Contribution to journalArticle

Ramanathan, Ramesh K. ; Kirkpatrick, D. Lynn ; Belani, Chandra P. ; Friedland, David ; Green, Sylvan B. ; Chow, Hsiao-Hui ; Cordova, Catherine A. ; Stratton, Steven P ; Shadow, Elizabeth R. ; Baker, Amanda F ; Dragovich, Tomislav. / A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 7. pp. 2109-2114.
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abstract = "Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1. Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks. Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon (<3{\%} of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the Cmax of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner. Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m 2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.",
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T1 - A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors

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AU - Kirkpatrick, D. Lynn

AU - Belani, Chandra P.

AU - Friedland, David

AU - Green, Sylvan B.

AU - Chow, Hsiao-Hui

AU - Cordova, Catherine A.

AU - Stratton, Steven P

AU - Shadow, Elizabeth R.

AU - Baker, Amanda F

AU - Dragovich, Tomislav

PY - 2007/4/1

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N2 - Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1. Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks. Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the Cmax of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner. Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m 2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.

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