Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma
Dan Liu, Chunguang Ma, Ping Lu, Jifang Gong, Dingwei Ye, Siyang Wang, Peijian Peng, Yuxian Bai, Yuqin Song, Jianhua Chen, Ou Jiang, Guojun Zhang, Yi Ba, Li Chen, Jianji Pan, Qi Li, Liling Zhang, Shanzhi Gu, Xianli Yin, Bangwei Cao, Weiqing Han, Haiying Dong, Jianming Guo, Huilai Zhang, Hang Su, Yongsheng Jiang, Weiwei Ouyang, Lulin Ma, Yan Sun, Feng Zhang, Jun Lv, Yabing Guo, Chongyuan Xu, Junyuan Qi, Li Wang, Xiang Wang, Zhen Liu, Lin Shen, Dan Liu, Chunguang Ma, Ping Lu, Jifang Gong, Dingwei Ye, Siyang Wang, Peijian Peng, Yuxian Bai, Yuqin Song, Jianhua Chen, Ou Jiang, Guojun Zhang, Yi Ba, Li Chen, Jianji Pan, Qi Li, Liling Zhang, Shanzhi Gu, Xianli Yin, Bangwei Cao, Weiqing Han, Haiying Dong, Jianming Guo, Huilai Zhang, Hang Su, Yongsheng Jiang, Weiwei Ouyang, Lulin Ma, Yan Sun, Feng Zhang, Jun Lv, Yabing Guo, Chongyuan Xu, Junyuan Qi, Li Wang, Xiang Wang, Zhen Liu, Lin Shen
Abstract
Background: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity.
Aim: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors.
Methods: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively.
Results: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response.
Conclusion: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.
Trial registration: ClinicalTrials.gov NCT03713905.
Keywords: Efficacy; Phase Ia/Ib study; Programmed death-1 monoclonal antibody; Safety; Solid tumors.
Conflict of interest statement
Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zhen Liu declared employment by Guangzhou Gloria Biosciences Co., Ltd. All the other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Source: PubMed