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 language | English (US) |
|---|---|
| Pages (from-to) | 631-641 |
| Number of pages | 11 |
| Journal | Investigational New Drugs |
| Volume | 31 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jun 2013 |
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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 journal › Article
}
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 -