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

Abstract

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 ∼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.

• Authors: K Yong, J Cavet, P Johnson, G Morgan, C Williams, D Nakashima, S Akinaga, H Oakervee, J Cavenagh
• Journal: British journal of cancer (Br J Cancer) Vol. 114 Issue 1 Pg. 7-13 (Jan 12 2016) ISSN: 1532-1827 [Electronic] England
• PMID: 26695442 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• HSP90 Heat-Shock Proteins
• KW-2478
• Morpholines

Topics

• Aged
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Lymphoma, Non-Hodgkin (drug therapy)
• Male
• Middle Aged
• Morpholines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Multiple Myeloma (drug therapy)