A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers

Amanda F Baker, K. N. Adab, N. Raghunand, Hsiao-Hui Chow, Steven P Stratton, S. W. Squire, M. Boice, L. A. Pestano, D. L. Kirkpatrick, T. Dragovich

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m2 /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non-bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF-2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies.

Original languageEnglish (US)
Pages (from-to)631-641
Number of pages11
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 2013

Fingerprint

Thioredoxins
Gastrointestinal Neoplasms
Fibroblast Growth Factor 2
Pharmacokinetics
Exhalation
Maximum Tolerated Dose
Intravenous Infusions
Vascular Endothelial Growth Factor A
Neoplasms
Appointments and Schedules
Therapeutics
Clinical Trials
Safety
Pharmaceutical Preparations

Keywords

  • GI Cancers
  • PX-12
  • Redox
  • Thioredoxin-1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers. / Baker, Amanda F; Adab, K. N.; Raghunand, N.; Chow, Hsiao-Hui; Stratton, Steven P; Squire, S. W.; Boice, M.; Pestano, L. A.; Kirkpatrick, D. L.; Dragovich, T.

In: Investigational New Drugs, Vol. 31, No. 3, 06.2013, p. 631-641.

Research output: Contribution to journalArticle

Baker, Amanda F ; Adab, K. N. ; Raghunand, N. ; Chow, Hsiao-Hui ; Stratton, Steven P ; Squire, S. W. ; Boice, M. ; Pestano, L. A. ; Kirkpatrick, D. L. ; Dragovich, T. / A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers. In: Investigational New Drugs. 2013 ; Vol. 31, No. 3. pp. 631-641.
@article{0df5c1c09b1242b890b98ac7654ae31c,
title = "A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers",
abstract = "We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m2 /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non-bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF-2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies.",
keywords = "GI Cancers, PX-12, Redox, Thioredoxin-1",
author = "Baker, {Amanda F} and Adab, {K. N.} and N. Raghunand and Hsiao-Hui Chow and Stratton, {Steven P} and Squire, {S. W.} and M. Boice and Pestano, {L. A.} and Kirkpatrick, {D. L.} and T. Dragovich",
year = "2013",
month = "6",
doi = "10.1007/s10637-012-9846-2",
language = "English (US)",
volume = "31",
pages = "631--641",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "3",

}

TY - JOUR

T1 - A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers

AU - Baker, Amanda F

AU - Adab, K. N.

AU - Raghunand, N.

AU - Chow, Hsiao-Hui

AU - Stratton, Steven P

AU - Squire, S. W.

AU - Boice, M.

AU - Pestano, L. A.

AU - Kirkpatrick, D. L.

AU - Dragovich, T.

PY - 2013/6

Y1 - 2013/6

N2 - We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m2 /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non-bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF-2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies.

AB - We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m2 /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non-bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF-2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies.

KW - GI Cancers

KW - PX-12

KW - Redox

KW - Thioredoxin-1

UR - http://www.scopus.com/inward/record.url?scp=84879123031&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879123031&partnerID=8YFLogxK

U2 - 10.1007/s10637-012-9846-2

DO - 10.1007/s10637-012-9846-2

M3 - Article

C2 - 22711542

AN - SCOPUS:84879123031

VL - 31

SP - 631

EP - 641

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 3

ER -