Abstract 473P
Background
TGF-β signaling pathway activation promotes tumor metastasis and progression, mediates epithelial-mesenchymal transmission (EMT) suppressing immunosurveillance in advanced tumors. GFH018, a novel small molecule that inhibits TGF-βRI kinase, blocks TGF-β signaling transduction thus inhibits tumor progression. In preclinical models, GFH018 showed significant anti-tumor activity as monotherapy and in combination with an anti-PD-1 antibody. This phase I study will assess the safety, pharmacokinetics (PK), and preliminary efficacy of GFH018 monotherapy in pts with advanced solid tumors.
Methods
This is an open-label, multicenter study comprising of a modified 3 + 3 dose escalation part followed by an expansion part. The starting dose was 5 mg and up to 8 cohorts were planned. Eligible pts with advanced solid tumors failed to standard therapies were administrated with GFH018 BID, 14d on/14d off in 28-day cycles. AEs were graded per NCI-CTCAE v5.0. PK analysis was performed using a non-compartmental method. Efficacy was evaluated per RECIST 1.1.
Results
As of Jan 25, 2022, 39 pts (5 mg [n=4]; 10 mg [n=3]; 20mg [n=4]; 30 mg [n=7]; 40, 50 mg [n=4 each]; 65 mg [n=6] and 85 mg [n=7]) were sequentially enrolled in the dose escalation part. The median lines of prior therapy were ≥ 3. No DLT was observed and the MTD was not reached. No pts discontinued due to AE. 35 pts (89.7%) had at least one related AE and 2 (5.1%) experienced ≥ grade (G) 3 related AE. The most common related AEs (all G/≥G3) were proteinuria (28.2%/2.6%), AST increased (15.4%/0), ALT increased (12.8%/0), anemia (12.8%/0), lymphocyte count decreased (10.3%/2.6%), ALP increased (10.3%/0), and LDH increased (10.3%/0). PK of GFH018 was linear and dose-independent with mean half-life in the range of 3.11 h- 8.30 h. Accumulation in PK exposure was limited post multiple dosing. Of 24 evaluable pts, 5 achieved stable disease (SD). A pt with thymic carcinoma receiving 50 mg achieved a durable SD with tumor shrinkage (maximum lesion decreased by 18.4%) and has stayed on treatment for 185 days as of the data cut-off date.
Conclusions
GFH018 shows a favorable safety profile and is now being tested in combination with an anti-PD-1 antibody in patients with advanced malignancies. Further studies are warranted.
Clinical trial identification
NCT05051241.
Editorial acknowledgement
Legal entity responsible for the study
GenFleet Therapeutics (Zhejiang) Co., Ltd.
Funding
GenFleet Therapeutics (Zhejiang) Co., Ltd.
Disclosure
H. Ren, H. Zhang, S. Wang, Y. Zhang: Financial Interests, Personal and Institutional, Full or part-time Employment: GenFleet Therapeutics, Inc. All other authors have declared no conflicts of interest.