Phase I dose escalation and pharmokinetic study of a modified schedule of 14-o-phosphonooxymethyltriptolide.

TPS472 Background: We are conducting a phase I trial of a modified dosing schedule of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma. We have previously presented our results from the initial phase I study of 27 patients using a daily dosing schema. That study demonstrated promising clinical activity with documented reductions in HSP70 levels. The common and dose limiting toxicity was neutropenia, which though cumulative, was also rapidly reversible early in the course of therapy with brief treatment interruptions. Several patients with disease control in the highest dose cohorts (0.67 and 0.8 mg/m2) progressed after dose reductions o...