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Mol Cancer Ther. 2019 Mar;18(3):531-540. doi: 10.1158/1535-7163.MCT-18-0831. Epub 2019 Jan 24.

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors.

Author information

1
Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
2
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
3
Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. nbryamam@ncc.go.jp.
4
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
5
Department of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo, Japan.
6
Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
7
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
8
Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan.
9
Department of Hepatobiliary Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan.
10
Clinical Pharmacology and Trials, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
11
Department of Haematology-Oncology, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
12
National University Health System, Singapore.
13
Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.
14
Taiho Oncology, Inc., Princeton, New Jersey.

Abstract

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/m2/day for QD, and 210.7 mg/m2/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 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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