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.
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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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