TRX518 is a humanized monoclonal antibody engineered to enhance immune responses against cancer. Developed by Leap Therapeutics, it is being investigated for the treatment of patients with advanced solid tumors.

How TRX518 works

TRX518 targets a protein called glucocorticoid-induced TNF-superfamily receptor (GITR), which is found in multiple types of specialized immune cells called T-cells. TRX518 works by blocking the interaction of GITR with its ligand. This activates tumor-antigen-specific T effector cells, reduces the immunosuppression caused by inappropriately activated T regulatory cells in tumors, and increases the elimination of cancerous cells. These activities also are found to generate anti-tumor immunity, which is believed to aid in the treatment of cancer.

TRX518 in clinical trials

TRX518 is being studied in two repeat-dose clinical trials in patients with solid tumors in the U.S. The safety, tolerability, pharmacokinetics (the movement inside the body), and pharmacodynamics (the effect on the body) of TRX518 are currently being investigated in an open-label, non-randomized single group Phase 1 single dose escalation study (NCT01239134) in patients diagnosed with stage 3 or stage 4 melanoma or other solid tumors that cannot be removed with surgery.

The safety of TRX518 also is being investigated in a two-part, Phase 1 (NCT02628574) dose escalation study of multi-dose TRX518 in adults diagnosed with advanced solid tumors. The primary outcome of this study is to measure adverse changes in health or side effects in patients from the initiation of the study through to completion or premature withdrawal. This study, which is recruiting participants in the U.S., will be conducted in two parts. The dose escalation will be performed in part A where patients will be administered consecutively with ascending doses of the treatment in order to evaluate safety and dose-limiting toxicities (DLTs), and identify the maximum tolerated dose (MTD) or maximum administered dose (MAD). Once the MTD has been identified, a new group of participants who will receive multi-doses of TRX518 monotherapy at the MTD will be enrolled. This will be part B of the study during which different ascending doses of TRX518 will be compared to determine the effects of TRX518 on solid tumors.

Early data from these Phase 1 trials were presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) and showed that a single dose of TRX518 was safe and well-tolerated.

Updated clinical Phase 1 data were presented at the 2017 American Association for Cancer Research (AACR) and revealed that TRX518 led to a reduction in immunosuppressive regulatory T-cells in patients’ tumor and increased cell death in regulatory T-cells. It also was found that TRX518 had a direct effect of GITR simulation on human regulatory T-cells, a mechanism which is thought to be an important therapeutic tool to generate anti-tumor immunity and to be considered for immune therapy-based combination trials in the future.


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