Background: TGF-β signaling pathway activation inhibits anti-tumor response, promoting tumor progression and metastasis. GFH018, a small molecule inhibiting TGF-βRI kinase, blocks TGF-β signaling transduction thus downregulates its pathway. GFH018 had significant growth inhibitory effects on several in vivo tumor models as monotherapy and demonstrated synergistic effects combined with anti-PD-1 antibody. This phase I study assessed safety, PK, and preliminary efficacy of GFH018 in pts with advanced solid tumors. Here we report the final results from the completed study. Methods: The study includes a modified 3 + 3 dose escalation and an expansion part. Adult pts with advanced solid tumors failed to standard treatments were enrolled. The starting dose was 5 mg and up to 8 cohorts were planned. In the escalation part, pts were administrated with GFH018 BID (14d-on/14d-off) two days after receiving single dose orally on C1D1. The subsequent cycle was 28 days. The safety of 85 mg BID 7d-on/7d-off was also explored. AEs were graded per NCI-CTCAE v5.0. PK was analyzed using a non-compartmental method. Efficacy was evaluated per RECIST 1.1. Blood samples were collected for biomarker analysis. Results: From Aug 1, 2019 to Aug 11, 2022, fifty pts (14d-on/14d-off: 5 mg [n = 4], 10 mg [n = 3], 20mg [n = 4], 30 mg [n = 7], 40 mg [n = 4], 50 mg [n = 4], 65 mg [n = 6] and 85 mg [n = 12]; 7d-on/7d-off: 85 mg [n = 6]) were enrolled. Thirty-seven pts (74.0%) had ≥3 prior systemic treatment lines. No DLT was observed, and the MTD was not reached. No significant cardiotoxicities or bleeding events were reported. Forty-three pts (86.0%) had at least one treatment related AE (TRAE), and 3 (6.0%) experienced ≥ G3 TRAEs. The most common TRAEs (all G/≥G3) were proteinuria (26.0%/2.0%), AST increased (18.0%/0), anemia (14.0%/2.0%), ALT increased (12.0%/0), GGT increased, ALP increased, and LDH increased (all 10.0%/0). Common TRAEs (≥2 pts) for 7d-on/7d-off was lymphocyte decreased (2/6) with no ≥ G3 reported. No significant differences were observed between the two regimens in safety. GFH018 was absorbed rapidly with median T_max of 0.50 ~0.96h and displayed a linear pharmacokinetic behavior with T_1/2 of 4.08~10.92 h (5~85 mg). Nine pts achieved stable disease (SD), among whom a pt with thymic carcinoma receiving 65 mg achieved tumor shrinkage (maximum target lesion decreased by 18.4%). Results for 85 mg BID, 14d-on/14d-off showed a DCR of 25.0%. The RP2D was 85 mg BID, 14d-on/14d-off. Serum TGF-β1 level was not associated with clinical responses. Available pharmacodynamic data of SMAD2 phosphorylation levels in peripheral blood mononuclear cells (PBMCs) were not reliable due to assay issues. Conclusions: GFH018 shows a favorable safety profile and preliminary anti-tumor activity. The clinical studies of GFH018 in combination with Toripalimab and with Toripalimab + concurrent chemoradiotherapy are ongoing. Clinical trial information: NCT05051241.