%0 Multicenter Study
%T First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-β receptor I inhibitor, in patients with advanced solid tumors.
%A Guo Y
%A Wang Z
%A Zhou H
%A Pan H
%A Han W
%A Deng Y
%A Li Q
%A Xue J
%A Ge X
%A Wang S
%A Wang J
%A Zhang Y
%A Zhao C
%A Zhu H
%A Wang Y
%A Shen H
%A Liu D
%A Li J
%J BMC Cancer
%V 24
%N 1
%D 2024 Apr 10
%M 38600507
%F 4.638
%R 10.1186/s12885-024-12216-7
%X <B>BACKGROUND: </B>Transforming growth factor-β (TGF-β) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-β pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-β signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors.<BR><B>METHODS: </B>This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis.<BR><B>RESULTS: </B>Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-β1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off.<BR><B>CONCLUSIONS: </B>GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies.<BR><B>BACKGROUND: </B>ClinicalTrial. gov ( https://www.<BR><B>RESULTS: </B>gov/ ), NCT05051241. Registered on 2021-09-02.