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Abstract Background: Gremlin-1 (GREM1), a member of the TGF-β superfamily, plays a key role in EMT, and cancer cell proliferation by binding to BMPs. GREM1 is widely expressed in various human cancers and TME stromal cells. Overexpression of GREM1 is correlated with poor prognosis. TST003 is a novel humanized IgG1 monoclonal antibody targeting GREM1 with high affinity and selectivity, and it blocks GREM1 binding to BMP2/4 resulting in enhanced BMP signaling. This study will investigate TST003’s safety, tolerability, and preliminary anti-tumor activity in patients with advanced solid tumors. Objectives: The primary objectives are to evaluate the safety and tolerability and determine the maximum tolerated dose and/or optimal biologic dose (s) of TST003. Secondary objectives include pharmacokinetic, pharmacodynamic and preliminary anti-tumor activity of TST003. A comprehensive biomarker plan will be implemented to analyze GREM1 expression, BMP signaling pathway, and tumor microenvironment with tumor tissues (including tumor cells, CAFs, Teff, Treg, MDSCs and TAMs), as well as circulating tumor DNA to explore the correlation among drug exposure, pharmacodynamic markers and clinical outcomes. Method: This is a first in human Phase 1 study in locally advanced or metastatic solid tumor subjects having tumor progression during or after prior therapies and have no standard therapy that could confer clinical benefit. It comprises of the Part 1 Dose Escalation and the Part 2 Pharmacodynamic Cohorts. Part 1 will evaluate sequential dose levels of 1, 3, 10, 20 and 30 mg/kg TST003 iv. , every three weeks as a single agent. The traditional “3+3” design were used for dose escalation of the first two cohorts (1 and 3 mg/kg), and Bayesian Optimal Interval (BOIN) Design with prespecified cohort size of 3 is used in the following cohorts. Part 2 will include 2 pharmacodynamic cohorts to evaluate the pharmacokinetic (PK) profile, pharmacodynamic (PD) markers, preliminary tumor response, as well as safety of TST003 as monotherapy in locally advanced or metastatic colorectal adenocarcinoma (CRC) subjects. The 2 doses used in the pharmacodynamic cohorts will be chosen from Part 1 and are expected to be within the pharmacologically active range based on nonclinical PK/PD modeling and available clinical PK/PD data from the ongoing study. Baseline GREM1 expression will be analyzed by immunohistochemistry. In each pharmacodynamic cohort, around 13-18 subjects will be enrolled to ensure at least 7 GREM1 positive subjects. Eligible subjects will receive TST003 until unacceptable toxicity or disease progression by RECIST v1. 1. The enrollment is ongoing in clinical centers in the US and China. No significant safety signals were reported in the first few patients treated with TST003. Clinical Trial Information: NCT05731271. Study Sponsor: Suzhou Transcenta Therapeutics Co. , Ltd. Citation Format: Ismael Rodriguez Rivera, Lin Shen, Shivaani Kummar, Minal Barve, Caroline Germa, Chuan Qi, Lei Chen, Jenny Milata, Jenny Yao, Li Shen, Xuelian Zhu. A first-in-human, open-label, multi-center phase 1 study of TST003, a GREM 1 inhibitor, in subjects with locally advanced or metastatic solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5977.
Rivera et al. (Fri,) studied this question.