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, H. H.Sherry Chow, Catherine A. Cordova, Steven P. Stratton, Elizabeth R. Shadow, Amanda Baker, Tomislav Dragovich

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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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ramanathan, Ramesh K. ; Kirkpatrick, D. Lynn ; Belani, Chandra P. ; Friedland, David ; Green, Sylvan B. ; Chow, H. H.Sherry ; Cordova, Catherine A. ; Stratton, Steven P. ; Shadow, Elizabeth R. ; Baker, Amanda ; 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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title = "A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors",
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.",
author = "Ramanathan, {Ramesh K.} and Kirkpatrick, {D. Lynn} and Belani, {Chandra P.} and David Friedland and Green, {Sylvan B.} and Chow, {H. H.Sherry} and Cordova, {Catherine A.} and Stratton, {Steven P.} and Shadow, {Elizabeth R.} and Amanda Baker and Tomislav Dragovich",
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Ramanathan, RK, Kirkpatrick, DL, Belani, CP, Friedland, D, Green, SB, Chow, HHS, Cordova, CA, Stratton, SP, Shadow, ER, Baker, A & Dragovich, T 2007, 'A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors', Clinical Cancer Research, vol. 13, no. 7, pp. 2109-2114. https://doi.org/10.1158/1078-0432.CCR-06-2250

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, H. H.Sherry; Cordova, Catherine A.; Stratton, Steven P.; Shadow, Elizabeth R.; Baker, Amanda; Dragovich, Tomislav.

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

Research output: Contribution to journalArticle

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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

AU - Ramanathan, Ramesh K.

AU - Kirkpatrick, D. Lynn

AU - Belani, Chandra P.

AU - Friedland, David

AU - Green, Sylvan B.

AU - Chow, H. H.Sherry

AU - Cordova, Catherine A.

AU - Stratton, Steven P.

AU - Shadow, Elizabeth R.

AU - Baker, Amanda

AU - Dragovich, Tomislav

PY - 2007/4/1

Y1 - 2007/4/1

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.

AB - 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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