Safety, tolerability, and pharmacokinetics/pharmacodynamics of JMT103 in patients with bone metastases from solid tumors

Xu Liang, Junli Xue, Xiaoxiao Ge, Jin Li, Huiping Li, Liqiong Xue, Lijun Di, Wenbo Tang, Guohong Song, Qun Li, Hanfang Jiang, Wei Zhao, Fengjuan Lin, Bin Shao, Xiugao Yang, Zhufeng Wu, Tianyi Zhang, Chenchen Wang, Ye Guo, Xu Liang, Junli Xue, Xiaoxiao Ge, Jin Li, Huiping Li, Liqiong Xue, Lijun Di, Wenbo Tang, Guohong Song, Qun Li, Hanfang Jiang, Wei Zhao, Fengjuan Lin, Bin Shao, Xiugao Yang, Zhufeng Wu, Tianyi Zhang, Chenchen Wang, Ye Guo

Abstract

Bone metastases are common complications of solid tumors. The outcome is poor despite major progress in cancer therapies. We describe a multicenter, open-label, phase 1, dose escalation and expansion trial of JMT103, a novel fully humanized receptor activator of nuclear factor kappa-B ligand (RANKL)-targeting monoclonal antibody, in adults with bone metastases from solid tumors. The study assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of JMT103. Patients received JMT103 at doses of 0.5, 1.0, 2.0, and 3.0 mg/kg every 4 weeks for 3 cycles. Among 59 patients enrolled, 20 and 39 patients participated in the dose-escalation and dose-expansion phases, respectively. One dose-limiting toxicity was observed at 2.0 mg/kg. The maximum tolerated dose was not determined. Treatment-related adverse events were reported in 29 (49.2%) patients, most commonly hypophosphatemia (30.5%), hypocalcemia (23.7%), and hypermagnesemia (10.2%). No treatment-related serious adverse events were reported. Two patients died due to disease progression, which were attributed to gastric cancer and lung neoplasm malignant respectively. Dose proportionality occurred between exposure levels and administered dose was within a dose range of 0.5 to 3.0 mg/kg. The suppression of urinary N-telopeptide corrected for creatinine was rapid, significant, and sustained across all doses of JMT103, with the median change from baseline ranging from -61.4% to -92.2% at day 141. JMT103 was well tolerated in patients with bone metastases from solid tumors, with a manageable safety profile. Bone antiresorptive activity shows the potential of JMT103 for treatment of bone metastases from solid tumors. Registration No.: NCT03550508; URL: https://www.clinicaltrials.gov/.

Keywords: JMT103; N-telopeptide; RANKL; bone metastasis; pharmacokinetics; phase 1 study.

Conflict of interest statement

XY, ZW, TZ, and CW were employed by CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. JL serves as a consultant to Hutchison, Eli Lilly, and CTTQ. YG received speaker honoraria from Merck Serono, Roche, MSD, BMS, and serves on scientific advisory board for Merck Serono, MSD, Bayer, and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Shanghai JMT-BIO technology Co., Ltd. The funder had the following involvement with the study: study design, collection, analysis, interpretation of data, and the decision to submit it for publication.

Copyright © 2022 Liang, Xue, Ge, Li, Li, Xue, Di, Tang, Song, Li, Jiang, Zhao, Lin, Shao, Yang, Wu, Zhang, Wang and Guo.

Figures

Figure 1
Figure 1
Study flow and patient disposition. SAS, safety analysis set; PKAS, PK analysis set; PDAS, PD analysis set; DLTAS, DLT analysis set; PD, pharmacodynamic; PK, pharmacokinetic; s.c., subcutaneous; Q4W, every 4 weeks.
Figure 2
Figure 2
Mean concentration-time profiles following subcutaneous administration of JMT103 in patients with bone metastasis from solid tumors. (A) Serum concentration-time profile of JMT103 after single-dose administration; (B) serum concentration-time profile of JMT103 after multiple-dose administration. SD, standard deviation. a means pre-dose;b means post-dose.
Figure 3
Figure 3
Effect of JMT103 on the concentration of (A) uNTx/Cr; (B) sCTx-I; (C) TRAP5b; (D) bALP; (E) iPTH; (F) adjCa. uNTx, urinary N-telopeptide; Cr, urinary creatinine; sCTx-I, serum C-telopept. TRAP5b, tartrate-resistant acid phosphatase 5b; bALP, bone alkaline phosphatase; iPTH, intact parathyroid hormone; adjCa, serum albumin-adjusted serum calcium.

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