First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-β receptor I inhibitor, in patients with advanced solid tumors
© 2024. The Author(s)..
BACKGROUND: 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.
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-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.
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
BMC cancer - 24(2024), 1 vom: 10. Apr., Seite 444 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guo, Ye [VerfasserIn] |
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| Links: |
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| Themen: |
Immunomodulation |
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| Anmerkungen: |
Date Completed 12.04.2024 Date Revised 25.04.2024 published: Electronic ClinicalTrials.gov: NCT05051241 Citation Status MEDLINE |
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| doi: |
10.1186/s12885-024-12216-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-β receptor I inhibitor, in patients with advanced solid tumors |
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| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT05051241 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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-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 | ||
| 520 | |a CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrial. gov ( https://www | ||
| 520 | |a CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02 | ||
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| 650 | 4 | |a Tumor Microenvironment | |
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| 650 | 7 | |a Receptors, Transforming Growth Factor beta |2 NLM | |
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| 700 | 1 | |a Zhou, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Hongming |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Weidong |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yanhong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qun |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Junli |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Xiaoxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Congqiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Huaqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Haige |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jin |e verfasserin |4 aut | |
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