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/m(2) /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.

Figure 1

Cycle 1 individual concentration-time data from the 300 mg/m² every 2 weeks cohort.

Figure 2

Trx-1 plasma levels from frozen plasma of 89 healthy donors measured via ELISA. A cut off of 18 ng/mL (approximately 3-fold mean normal levels) was selected to stratify the pharmacodynamic data from this current PX-12 study.

Figure 3

Plasma Trx-1 levels over 4 cycles of bi-weekly PX-12 treatment in patients with pretreatment plasma Trx-1 over 18 ng/mL. 3B. Plasma Trx-1 levels over 4 cycles of bi-weekly or weekly PX-12 treatment in patients with pretreatment plasma Trx-1 under 18 ng/mL.

Figure 4

Plasma FGF-2 levels in patients with plasma Trx-1 values (Day 1) over or under 18 ng/mL. Only patients with evaluable starting FGF-2-2 levels are shown. In general, PX-12 treatment suppressed plasma FGF-2 in patients with high plasma Trx-1 yet had little effect on those patients with normal plasma Trx-1 levels.

Figure 5

Anatomic reference MRI images and corresponding pixel-by-pixel maps of K^trans in subject 02-012. Target tumor (arrow) K^trans was low at baseline, decreasing at 24 h post-infusion, increasing above baseline by 7 days post-infusion. The color legend for K^trans runs from 0.0 min⁻ (dark blue) through 0.6 min⁻ (yellow). K^trans results for all study subjects are summarized in Table 5.