Phase I Study of the Focal Adhesion Kinase Inhibitor BI 853520 in Japanese and Taiwanese Patients with Advanced or Metastatic Solid Tumors

Toshihiko Doi, James Chih-Hsin Yang, Kohei Shitara, Yoichi Naito, Ann-Lii Cheng, Akiko Sarashina, Linda C Pronk, Yoshito Takeuchi, Chia-Chi Lin, Toshihiko Doi, James Chih-Hsin Yang, Kohei Shitara, Yoichi Naito, Ann-Lii Cheng, Akiko Sarashina, Linda C Pronk, Yoshito Takeuchi, Chia-Chi Lin

Abstract

Background: Focal adhesion kinase (FAK) inhibitors have demonstrated anti-tumor activity preclinically and are currently being evaluated in humans. A first-in-human study evaluating the novel FAK inhibitor BI 853520 in a predominantly Caucasian population with advanced or metastatic non-hematologic malignancies demonstrated acceptable tolerability and favorable pharmacokinetics.

Objective: This study was undertaken to investigate the safety, tolerability, and maximum tolerated dose (MTD) of BI 853520 in Japanese and Taiwanese patients with advanced solid tumors.

Patients and methods: In this open-label, phase I, dose-finding study, BI 853520 was administered once daily (QD) in a continuous daily dosing regimen with 28-day cycles and escalating doses to sequential cohorts of patients. Twenty-one patients (62% male; median age 65 years) were treated at two sites in Japan and Taiwan.

Results: The median duration of treatment was 1.2 months (range 0.2-7.7). As no dose-limiting toxicities were observed during cycle 1 in the 50, 100, or 200 mg cohorts, the MTD of BI 853520 was determined to be 200 mg QD. Drug-related adverse events were reported in 19 patients (90%), and all except one were of grade 1 or 2. Pharmacokinetic parameters were supportive of a once-daily dosing schedule. A confirmed objective response rate of 5% and disease control rate of 29% were achieved; median duration of disease control was 3.7 months.

Conclusions: This trial demonstrated a manageable and acceptable safety profile, favorable pharmacokinetics, and potential anti-tumor activity of BI 853520 in pretreated Japanese and Taiwanese patients with advanced or metastatic solid tumors.

Clinical trials registration: NCT01905111.

Conflict of interest statement

James Chih-Hsin Yang has consulted for and received honoraria from Eli Lilly, Boehringer Ingelheim, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, AstraZeneca, Takeda, and Hansoh Pharmaceuticals. Kohei Shitara has consulted for or received honoraria from Astellas Pharma, Lilly, BMS, Takeda, Pfizer, Ono Pharmaceutical Co., Ltd., Novartis, AbbVie, and Yakult, and also reports research funding from Lilly, Ono Pharmaceutical Co., Ltd., Dainippon Sumoitomo Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, and MSD. Ann-Lii Cheng has consulted for or received honoraria from Bayer, BMS, Eisai, MSD, Merck, Novartis, BeiGene, and Ono Pharmaceutical Co., Ltd. Akiko Sarashina and Yoshito Takeuchi are employees of Nippon Boehringer Ingelheim Co., Ltd. Linda C. Pronk is an employee of Boehringer Ingelheim. Toshihiko Doi, Yoichi Naito, and Chia-Chi Lin declare that they have no conflicts of interest. This trial was sponsored by Nippon Boehringer Ingelheim. Co., Ltd. in Japan, and Boehringer Ingelheim Taiwan Ltd. in Taiwan. This work was supported by Boehringer Ingelheim, Ingelheim am Rhein, Germany. BI 853520 is an asset of Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
Arithmetic mean plasma concentration–time profiles of BI 853520 after single-dose and multiple-dose oral administration of 50, 100, and 200 mg once daily of BI 853520 in cycle 1: a linear scale (error bars represent standard deviation); and b logarithmic scale. a One patient was not evaluable for pharmacokinetic parameters due to incomplete data

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