First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß 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. METHODS: 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. RESULTS: 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-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

A phase I randomized, double-blinded, placebo-controlled study assessing the safety and pharmacokinetics of RIPK1 inhibitor GFH312 in healthy subjects.

Receptor-interacting protein kinase 1 (RIPK1) mediates necroptosis and inflammation in various pathophysiologies, emerging as a pharmacological target for neurodegenerative and inflammatory indications. This phase I, first-in-human, placebo-controlled study evaluated the safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GFH312, an RIPK1 inhibitor, in healthy adults. Subjects received GFH312 as a single ascending dose up to 500 mg (part I) or once-daily repeated doses up to 200 mg for 14 days (part II). PKs were assessed using plasma and cerebrospinal fluid (CSF); PDs were assessed by phospho-RIPK1 levels. Seventy-six subjects were enrolled between April 2021 and June 2022: 38 (part I) and 19 (part II) received GFH312; 14 and five received placebo, respectively. At least one treatment-emergent adverse event (TEAE) occurred in 42.1% (part I) and 63.2% (part II) of subjects receiving GFH312, compared with 42.9% and 40.0% of subjects receiving placebo, respectively. The most common TEAE was headache (21.1%). Two treatment-related TEAEs were reported in part I and four in part II. No serious TEAEs were reported. Systemic absorption was rapid; exposure (area under the concentration-time curve from time zero to the last measurable concentration and maximum plasma concentration) increased with dose level. The GFH312 CSF concentration post 100 mg single dose was approximately fourfold higher than the half maximal inhibitory concentration of human monocyte-derived macrophages necroptosis with expected central nervous system penetration. Subjects receiving GFH312 had decreased phospho-RIPK1 levels in peripheral blood mononuclear cells postdose. In conclusion, GFH312 was well-tolerated and demonstrated RIPK1 inhibition in healthy subjects. Ongoing studies will inform the use of GFH312 in potential indications.