Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 3, Pages 531-540Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-0831
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Funding
- Cancer Research UK
- Experimental Cancer Medicine Centre initiative
- Biomedical Research Centre grants
- Taiho Pharmaceutical Co., Ltd.
- Taiho Oncology, Inc.
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HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a 3+3 design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m(2)/day for QD, and 210.7 mg/m(2)/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD x 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor. This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.
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