Phase I Pharmacokinetic and Pharmacodynamic Study of the Heat Shock Protein 90 Inhibitor AT13387 in Patients with Refractory Solid Tumors.

3069 Background: AT13387 is a highly potent heat shock protein 90 (HSP90) inhibitor (IC50 0.7 nM) derived from Astex fragment chemistry platform, Pyramid. AT13387 suppresses client proteins for greater than 7 days in tumor cells, making it the longest acting agent reported to date. Methods: In this phase I dose escalation trial, AT13387 was administered as a 1-hr intravenous infusion on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle in a standard “3+3” design in order to determine MTD. Secondary endpoints included PK, PD and tolerability. Results: Between May 2008 and December 2009,21 patients with median age 57 (r 28-77) were treated with AT13387 over 5 dose levels, including 10, 20, 40, 80 and 120 mg/m2 twice weekly. No dose-limiting toxicities have been observed. The most frequent toxicities reported in the first eighteen patients were diarrhea (11/18, 61%) and fatigue (5/18, 28%) of mild or moderate severity. At the 120 mg/m2 dose level, reversible grade 1 visual changes were common, including blurred vision, flashes and delayed light dark/accommodation, occurring at day 11 or later. Evidence of HSP90 inhibition, manifest as an increase in HSP70 in PBMCs, was detected at all dose levels and exhibited dose dependence. Reductions in the expression of CDK4, raf-1 and phospho-AKT were also detected in PBMCs in a proportion of patients. PK parameters determined on days 1 and 18 of cycle 1 demonstrated exposure proportional to dose administered, without significant plasma accumulation with repeated administration. Clearance of AT13387 was independent of dose (mean 25 ml/min/kg). The best response in this heavily pre-treated population has been stable disease that persisted for at least six months in two patients (follicular cell carcinoma of the thyroid and metastatic uveal melanoma). Conclusions: Single-agent AT13387, administered as a twice-weekly infusion three weeks out of four, is well- tolerated at doses up to 120mg/m2. No hepatotoxicity has been observed. Favorable pharmacokinetics and expected pharmacodynamic endpoints have been demonstrated. Further schedule refinement may involve evaluation of twice-weekly dosing two weeks out of every three, as well as weekly administration. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Astex Therapeutics Astex Therapeutics Astex Therapetics, Astex Therapeutics Astex Therapeutics