GFH018, a small molecular inhibitor targeting TGF-βRI kinase, in patients with advanced solid tumors: final results of the phase I study.

person Ye Guo Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China info_outline Ye Guo, Zishu Wang, Huan Zhou, Hongming Pan, Weidong Han, Yanhong Deng, Yanqiao Zhang, Yue Zhang, Shuang Wang, Jing Wang, Huaqiang Zhu, Haige Shen, Yu Wang, Jin Li

Authors person Ye Guo Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China info_outline Ye Guo, Zishu Wang, Huan Zhou, Hongming Pan, Weidong Han, Yanhong Deng, Yanqiao Zhang, Yue Zhang, Shuang Wang, Jing Wang, Huaqiang Zhu, Haige Shen, Yu Wang, Jin Li Organizations Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangdong, China, The Affiliated Hospital of Harbin Medical University, Harbin, China, Clinical Department, GenFleet Therapeutics Inc., Shanghai, China, Translational Science, GenFleet Therapeutics Inc., Shanghai, China Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Zhejiang Genfleet Therapeutics Co., Ltd. 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.

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