A 2-stage controlled phase 1/2 study of STA-4783 in combination with paclitaxel in patients with advanced metastatic melanoma

Abstract

7561 Background: STA-4783 (S), a novel inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to upregulation of hsp70 in tumor cell lines. Xenograft modeling with solid tumor cell lines demonstrated dramatic antitumor activity in combination with paclitaxel (P). Mechanistic studies suggest that the P enhancement is immune-mediated, creating, in effect, a chemically-induced biochemotherapy. The combination of S and P has been studied in a Phase 1 trial with the drugs coadministered i.v. over 3 h every 3 weeks. Doses ranged from (S/P, mg/m2) 44/135 to 525/175. Based on dose-related HSP70 induction (evidence of biological activity) and demonstrated tolerability, we began a Phase 2 study of the combination in patients with metastatic melanoma. Methods: The study consists of an initial safety assessment of the weekly dose schedule for 3 weeks every 4 weeks at S 106 mg/m2 and P 80 mg/m2. S was then escalated to 213 mg/m2 in combination. The higher tolerated dose level was expanded to a total of 20 patients (Stage 1). The criterion for continuation to Stage 2 was >= 50% non-progression rate (NPR) at 2 months. Stage 2 is a randomized 2-arm study comparing the drug combination to P alone. A total of 78 patients are to be randomized 2:1 (combination:control). The primary endpoint is time to progression; secondary endpoints are response rate, survival, and quality of life. Pharmacodynamic parameters include pre- and post-dose measurements of NK cell activity in blood and, when possible, tumor biopsies. Results: A total of 7 patients were treated in the initial safety assessment, 3 at the lower dose level and 4 at the higher. In the absence of dose-limiting toxicities in either group, the higher dose level was chosen as the dose of interest and additional patients were enrolled to complete Stage 1. Adverse events seen were as expected for P chemotherapy administration. In preliminary evaluation of 20 patients, 11 were stable at 2 months, for 55% NPR. The randomized Stage 2 portion will proceed, pending confirmation of the stage 1 data. Conclusions: The addition of S to P was well-tolerated on the weekly schedule. Enrollment in the randomized portion will assess the activity of S + P vs. P alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta Synta