STA-4783 in combination with paclitaxel induces heat shock protein 70 (hsp70) in a phase I trial

Abstract

2011 Background: STA-4783 (S) is a bis-thiobenzoylhydrazide that promotes induction of hsp70 and enhances paclitaxel (P) antitumor efficacy in xenograft models. Its mechanism appears to be immunologic, involving stimulation of cytotoxic responses. Methods: A phase 1 trial was conducted in combination with P in advanced solid tumor patients. S and P were coadministered iv over 3 h every 3 weeks. Starting doses were 44 mg/m2 S and 135 mg/m2 P. P was then increased to 175 mg/m2, followed by escalation of S to establish the maximum tolerated dose based upon first cycle toxicity in 3–6 patients at each dose level. Pharmacokinetic (PK) studies were performed during cycle 1 using LC/MS assays to measure both compounds in plasma. Hsp70 was measured in plasma before and after treatment. Results: 35 patients have been evaluated at 8 dose levels. The S dose was escalated from 44 to 525 mg/m2 in combination with P 175 mg/m2. No serious adverse events specifically attributable to S have been observed. P related dose limiting toxicities occurred in a single patient in each of the top three dose levels (neutropenia, arthralgia, and febrile neutropenia with mucositis) resulting in cohort expansion. S exhibited linear PK that was unaffected by P dose. It was rapidly eliminated from plasma with terminal-phase half-life of 0.94 ± 0.23 h and total body clearance of 28 ± 8 l/h/m2. Its apparent volume of distribution was comparable to total body water (Vss, 23 ± 16 l/m2). P PK appeared to be moderately dependent on the S dose, as indicated by a significant trend toward decreasing clearance, an increase in peak plasma concentration and Vss, but without affecting the terminal phase half-life. These observations are consistent with competitive inhibition of P hepatic metabolism. Increased toxicity at higher dose levels was consistent with moderate increase in systemic exposure to P. Induction of hsp70 protein in plasma was dose-dependent peaking at 8 h after dosing. Conclusions: The S/P combination was well tolerated, with adverse events consistent with those expected for P alone. Phase 2 clinical trials are underway in NSCLC, melanoma, and soft-tissue sarcoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta Synta