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

Yong, K; Cavet, J; Johnson, P; Morgan, G; Williams, C; Nakashima, D; Akinaga, S; ... Cavenagh, J; + view all (2016) Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies. British Journal of Cancer , 114 (1) pp. 7-13. 10.1038/bjc.2015.422. Green open access

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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.

Type: Article
Title: Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/bjc.2015.422
Publisher version: http://dx.doi.org/10.1038/bjc.2015.422
Language: English
Additional information: This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, oncology, chaperone, Hsp90, KW-2478, multiple myeloma, phase, multiple-myeloma cells, protein 90 inhibitor, molecular chaperone, antitumor-activity, 17-demethoxygeldanamycin, 17-allylamino, combination, therapies, future
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10050072
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