Abstract B87: First-in-human phase I dose escalation study of TAS-116, a novel, orally active HSP90α and HSP90β selective inhibitor, in patients with advanced solid tumors
Authors: Shimomura Akihiko , Horiike Atsushi , Tambo Yuichi , Ohyanagi Fumiyoshi , Yanagitani Noriko , Kitazono Satoru , Fujiwara Yutaka , Tanabe Yuko , Ohkubo Shuichi , Yamamoto Noboru , Nishio Makoto 
Published: May 2016

Abstract
Purpose: TAS-116 is a potent non-ansamycin, non-purine, and non-resorcinol orally available highly selective inhibitor of HSP90α and HSP90β. The primary objective of this phase I first-in-human study was to determine maximum-tolerated dose (MTD) of two TAS-116 dosing regimens and estimate recommended phase 2 dose (RP2D) in patients with advanced solid tumors. Secondary objective was to investigate safety, pharmacokinetic and pharmacodynamic profiles.
Methods: Eligible patients included those 20 years or older of age with advanced solid tumor that was refractory to conventional treatment or for which no standard therapy existed and ECOG performance status of 0 or 1. TAS-116 was administered orally once daily (Step1) and then subsequently every other day (Step 2) of a 21-day cycle in an accelerated titration dose escalation and a standard 3+3 dose escalation, respectively. Pharmacokinetics was measured after single and multiple dose. Pharmacodymanics was assessed by HSP70 induction in peripheral blood mononuclear cells (PBMCs).
Results: As of 17 Jun 2015, 16 patients were enrolled in Step 1 followed by 3 in Step 2. (57% male, median age of 56, 70% PS 0). The numbers of types of tumors were 13 with non-small cell lung cancer (NSCLC), 2 with gastrointestinal stromal tumor (GIST), 2 with thymic carcinoma, and 2 with others. In Step 1, TAS-116 was evaluated at 7 dose levels of 4.8 to 150.5 mg/m2. The most common treatment related adverse events were increased creatinine, diarrhea, increased alkaline phosphatase, night blindness, nausea, anorexia and skin rash. Dose limiting toxicities (DLTs) occurred in 4 patients at 107.5 mg/m2 and 150.5 mg/m2, with grade 3 night blindness and visual disorder, grade 3 AST/ ALT/ gamma-GTP elevations, and grade 3 anorexia. Night blindness and visual disorder including grade 3 were reversible when study drug was interrupted. 107.5 mg/m2 was determined as the once daily MTD and additional patients are being investigated at this dose to confirm tolerability. TAS-116 exposure was increased dose-dependently without unexpected accumulation after repeated administrations. HSP70 induction in PBMC was observed, indicative of target engagement. Of 16 evaluable patients on once daily dosing, there was two confirmed partial response (GIST and NSCLC). Five patients had stable disease more than 12 weeks.
Conclusions: TAS-116 administered once daily has an acceptable toxicity profile and the MTD was determined as 107.5 mg/m2. Preliminary antitumor activity was demonstrated with evidence of target engagement. The dose escalation study administered every other day is ongoing and the MTD will be determined.
Clinical trial information: JapicCTI-142444.
Citation Format: Akihiko Shimomura, Atsushi Horiike, Yuichi Tambo, Fumiyoshi Ohyanagi, Noriko Yanagitani, Satoru Kitazono, Yutaka Fujiwara, Yuko Tanabe, Shuichi Ohkubo, Noboru Yamamoto, Makoto Nishio. First-in-human phase I dose escalation study of TAS-116, a novel, orally active HSP90α and HSP90β selective inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B87.