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|Ref Type||Journal Article|
|Authors||Yong K, Cavet J, Johnson P, Morgan G, Williams C, Nakashima D, Akinaga S, Oakervee H, Cavenagh J|
|Title||Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies.|
|Journal||British journal of cancer|
|Date||2016 Jan 12|
|Abstract Text||KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.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.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.Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||multiple myeloma||not applicable||KW-2478||Phase I||Actionable||In a Phase I clinical trial, KW-2478 demonstrated safety and preliminary efficacy in patients with multiple myeloma, with 95.2% (20/21) of patients achieving stable disease (PMID: 26695442).||26695442|
|Unknown unknown||non-Hodgkin lymphoma||not applicable||KW-2478||Phase I||Actionable||In a Phase I clinical trial, KW-2478 demonstrated safety and preliminary efficacy in patients with non-Hodgkin lymphoma, with 100% (4/4) of patients achieving stable disease (PMID: 26695442).||26695442|