Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies

Background: KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor. Methods: In this phase I, multicentre study, KW-2478 was administered intravenously over 1 h at doses ranging from 14 to 176 mg m-(2) once daily on days 1-5 of a 14-day cycle in a standard 3 + 3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with >= 2 regimens. Results: There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of similar to 6 h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses >= 71 mg m(-2). Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for >= 6 months. Conclusions: Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.