Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies
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 ∼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.
Aged, Female, HSP90 Heat-Shock Proteins, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Morpholines, Multiple Myeloma, Clinical Trial, Phase I, Journal Article, Multicenter Study
7-13
Yong, K.
01b5d56e-a451-41e3-9c8f-8491ae03fb5c
Cavet, J.
09c53769-0743-4b9d-bcc7-ba68e29f7a7c
Johnson, P.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Morgan, G.
39504ae7-2828-4dd0-a970-02ef0676949c
Williams, C.
ac99b1df-f8a8-44d4-b21c-745488c4bb5c
Nakashima, D.
6696a7e8-7aaa-4550-bcae-9ba8f741e4ba
Akinaga, S.
b44da10f-4de4-4158-9fc7-4af121829f09
Oakervee, H.
b3efdff9-f127-46b4-bbb1-a6386cd11f14
Cavenagh, J.
c50d6e67-15c2-4b22-bbde-92903b0e7ccf
12 January 2016
Yong, K.
01b5d56e-a451-41e3-9c8f-8491ae03fb5c
Cavet, J.
09c53769-0743-4b9d-bcc7-ba68e29f7a7c
Johnson, P.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Morgan, G.
39504ae7-2828-4dd0-a970-02ef0676949c
Williams, C.
ac99b1df-f8a8-44d4-b21c-745488c4bb5c
Nakashima, D.
6696a7e8-7aaa-4550-bcae-9ba8f741e4ba
Akinaga, S.
b44da10f-4de4-4158-9fc7-4af121829f09
Oakervee, H.
b3efdff9-f127-46b4-bbb1-a6386cd11f14
Cavenagh, J.
c50d6e67-15c2-4b22-bbde-92903b0e7ccf
Yong, K., Cavet, J., Johnson, P., Morgan, G., Williams, C., Nakashima, D., Akinaga, S., Oakervee, H. and Cavenagh, J.
(2016)
Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.
British Journal of Cancer, 114 (1), .
(doi:10.1038/bjc.2015.422).
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.
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bjc2015422a
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More information
Accepted/In Press date: 26 October 2015
e-pub ahead of print date: 22 December 2015
Published date: 12 January 2016
Keywords:
Aged, Female, HSP90 Heat-Shock Proteins, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Morpholines, Multiple Myeloma, Clinical Trial, Phase I, Journal Article, Multicenter Study
Identifiers
Local EPrints ID: 413483
URI: http://eprints.soton.ac.uk/id/eprint/413483
ISSN: 0007-0920
PURE UUID: 7039bcb4-3a7f-4d04-9ab9-70e701153d04
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Date deposited: 24 Aug 2017 16:31
Last modified: 16 Mar 2024 03:00
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Contributors
Author:
K. Yong
Author:
J. Cavet
Author:
G. Morgan
Author:
C. Williams
Author:
D. Nakashima
Author:
S. Akinaga
Author:
H. Oakervee
Author:
J. Cavenagh
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