A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination

Q4 · MEDICINE

Article

Author: Linda A. Pestano ; Amanda F. Baker ; Jose M. Guillen ; Ramesh K. Ramanathan ; Sylvan Green ; James Abbruzzese ; Tomislav Dragovich ; Daniel D. Von Hoff ; Lynn Kirkpatrick

PURPOSEThis study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).METHODSPX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued.RESULTSPlasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively.CONCLUSIONSDue to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

01 Jan 2008·Molecular Cancer TherapeuticsQ2 · MEDICINE

Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α

Q2 · MEDICINE

Article

Author: Spivak-Kroizman, Taly ; Kirkpatrick, D. Lynn ; Williams, Ryan R. ; Koh, Mei Y. ; Venturini, Sara ; Powis, Garth ; Welsh, Sarah

AbstractWe have reported previously that PX-478 (S-2-amino-3-[4′-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1α (HIF-1α) within the tumor. We now report that PX-478 inhibits HIF-1α protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1α inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1α mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5′ untranslated region of HIF-1α. Moreover, to a lesser extent, PX-478 also inhibits HIF-1α deubiquitination resulting in increased levels of polyubiquitinated HIF-1α. The inhibitory effect of PX-478 on HIF-1α levels is primarily due to its inhibition of translation because HIF-1α translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1α at multiple levels that together or individually may contribute to its antitumor activity against HIF-1α-expressing tumors. [Mol Cancer Ther 2008;7(1):90–100]

01 Apr 2007·Clinical Cancer ResearchQ1 · MEDICINE

A Phase I Pharmacokinetic and Pharmacodynamic Study of PX-12, a Novel Inhibitor of Thioredoxin-1, in Patients with Advanced Solid Tumors

Q1 · MEDICINE

Article

Author: Chow, H-H. Sherry ; Friedland, David ; Kirkpatrick, D. Lynn ; Sharlow, Elizabeth R. ; Belani, Chandra P. ; Ramanathan, Ramesh K. ; Green, Sylvan B. ; Dragovich, Tomislav ; Cordova, Catherine A. ; Stratton, Steven P. ; Baker, Amanda

AbstractPurpose: 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/m2 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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