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Clinical Trial
. 2016 Oct;34(5):596-603.
doi: 10.1007/s10637-016-0371-6. Epub 2016 Jul 1.

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors

Hidenori Mizugaki  1 , Noboru Yamamoto  2 , Haruyasu Murakami  3 , Hirotsugu Kenmotsu  3 , Yutaka Fujiwara  1 , Yoshimasa Ishida  4 , Tomohisa Kawakami  4 , Toshiaki Takahashi  3
Affiliations
Clinical Trial

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors

Hidenori Mizugaki et al. Invest New Drugs. 2016 Oct.

Abstract

Background Atezolizumab is an engineered immunoglobulin monoclonal antibody that targets the programmed death-1/programmed death-ligand 1 pathway. Methods In this phase I dose-finding study, we assessed the safety, feasibility, pharmacokinetics (PK), and exploratory anti-tumor activity of atezolizumab monotherapy up to 20 mg/kg in Japanese patients with advanced solid tumors who had failed standard therapy or for whom there is no standard therapy. Results Six patients were enrolled and received intravenous atezolizumab every 3 weeks (q3w) at doses of 10 or 20 mg/kg. Tumor types were non-small cell lung cancer (n = 3), melanoma (n = 1), pancreatic cancer (n = 1), and thymic cancer (n = 1). No dose-limiting toxicities were observed. All adverse events (AEs) were grade 1 or 2 in severity. No discontinuations or deaths due to AEs were observed. As of the data cutoff, no partial responses were observed; however, stable disease was observed in all six patients. The maximum mean serum atezolizumab concentration was 220 μg/mL (SD ± 21.9), with 10-mg/kg dosing and 536 μg/mL (SD ± 49.4) with 20-mg/kg dosing. Three patients were still on treatment, and three of the six had achieved a progression-free survival of >12 months. Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab.

Keywords: Atezolizumab; Pharmacokinetics; Phase I; Safety; Solid tumors.

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Conflict of interest statement

Compliance with ethical standards Conflicts of interest Hidenori Mizugaki has nothing to disclose. Noboru Yamamoto reports grants from Chugai, grants from Eli Lilly, grants from Taiho, grants from Eisai, grants from Quintiles, grants from Astellas, grants from BMS, grants from Novartis, grants from Daiichi-Sankyo, grants from Pfizer, grants from Boehringer Ingelheim, grants from Kyowa-Hakko Kirin, grants from Bayer, outside the submitted work. Haruyasu Murakami reports personal fees from Chugai, outside the submitted work; Hirotsugu Kenmotsu reports personal fees from Chugai Pharmaceutical Co, Ltd., outside the submitted work. Yutaka Fujiwara reports grants from AstraZeneca, grants from Eli Lilly, grants from Eisai, grants from MerckSerono, grants from Chugai, grants from GlaxoSmithKline, outside the submitted work. Yoshimasa Ishida is a full time employee of Chugai Pharmaceutical. Tomohisa Kawakami is a full time employee of Chugai Pharmaceutical. Toshiaki Takahashi reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Boehringer Ingelheim Japan, INC, outside the submitted work. Ethical approval Written informed consent was obtained from all patients. This study was approved by the institutional review board at the National Cancer Center and Shizuoka Cancer Center and was conducted in accordance with Japanese Good Clinical Practice (GCP) guidelines. The study was conducted in compliance with the Declaration of Helsinki, the study protocol, the standards stipulated in Paragraph 3 of Article 14 and Article 80–2 of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Pharmaceuticals and Medical Devices Act), and the Ministerial Ordinance on Good Clinical Practice for Drugs (GCP).

Figures

Fig. 1
Fig. 1
Mean ± SD serum atezolizumab concentration–time profile (semi-log scale) at first infusion (a) and over 18 cycles (b)
Fig. 2
Fig. 2
Duration of progression-free survival * Censored observation. NSCLC non-small cell lung cancer, PFS progression-free survival
See this image and copyright information in PMC

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