Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer

Takeshi Masuda; Taizo Hirata; Tomohiro Sakamoto; Yukari Tsubata; Eiki Ichihara; Toshiyuki Kozuki; Hiroyasu Shoda; Masanori Motonaga; Takako Yoshida; Miki Fukutani; Kazue Tsuji-Takayama; Atsushi Tamura; Harunobu Amagase; Hideki Fujihara; Gaku Aoki; Tomoyuki Akita; Yasushi Orihashi; Toshio Miyata; Noboru Hattori

doi:10.21037/jtd-23-1858

Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer

J Thorac Dis. 2024 May 31;16(5):3381-3388. doi: 10.21037/jtd-23-1858. Epub 2024 May 27.

Authors

Takeshi Masuda¹, Taizo Hirata², Tomohiro Sakamoto³, Yukari Tsubata⁴, Eiki Ichihara⁵, Toshiyuki Kozuki⁶, Hiroyasu Shoda⁷, Masanori Motonaga², Takako Yoshida², Miki Fukutani², Kazue Tsuji-Takayama⁸, Atsushi Tamura², Harunobu Amagase², Hideki Fujihara², Gaku Aoki², Tomoyuki Akita⁹, Yasushi Orihashi², Toshio Miyata¹⁰, Noboru Hattori¹¹

Affiliations

¹ Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.
² Clinical Research Center in Hiroshima University Hospital, Hiroshima, Japan.
³ Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
⁴ Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan.
⁵ Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan.
⁶ Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
⁷ Department of Respiratory Medicine, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
⁸ Research Strategy and Promotion Division in Hiroshima University, Hiroshima, Japan.
⁹ Department of Epidemiology, Infectious Disease Control and Prevention, Graduate school of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
¹⁰ Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹¹ Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Abstract

Background: There is no established standard 3^rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1^st or 2^nd line treatment are administrated as 3^rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3^rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies.

Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3^rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years.

Discussion: Currently, there is no standard 3^rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication.

Trial registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

Keywords: Non-small cell lung cancer (NSCLC); TM5614; anti-programmed death-1 antibody; nivolumab; plasminogen activator inhibitor-1 (PAI-1).