PDF(Pubmed)
Abstract：
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.
BACKGROUND: ClinicalTrial. gov ( https://www.
RESULTS: gov/ ), NCT05051241. Registered on 2021-09-02.
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.
BACKGROUND: ClinicalTrial. gov ( https://www.
RESULTS: gov/ ), NCT05051241. Registered on 2021-09-02.
摘要：
背景：转化生长因子-β（TGF-β）是一种具有多种功能的细胞因子，包括细胞生长调节，细胞外基质的产生，血管生成稳态调节等。TGF-β途径激活促进肿瘤转移/进展并介导上皮-间质传递抑制晚期肿瘤的免疫监视。GFH018,一种小分子阻断TGF-β信号转导的抑制剂,抑制晚期癌症的进展和/或转移。这项首次在人体中的研究评估了安全性，耐受性,药代动力学（PK），GFH018单药治疗晚期实体瘤的疗效。
方法：第一阶段，开放标签，多中心研究使用改良的3+3剂量递增和扩展设计。纳入患有未达到标准治疗的晚期实体瘤的成年患者。从5毫克开始，评估了高达85mg的8个剂量水平。患者在第1周期第1天单剂量后第4天开始接受GFH018BID(14d-开/14d-关)。随后的周期定义为28天。该研究还探讨了85mgBID7d-on/7d-off的安全性。使用NCI不良事件标准（NCI-CTCAEv5.0）对不良事件进行分级。使用非隔室方法分析PK。使用RECIST1.1评价疗效。收集血液样品用于生物标志物分析。
结果：50名患者被纳入并接受了至少一个剂量的GFH018。没有发生剂量限制性毒性，未达到最大耐受剂量。43例患者（86.0％）至少有一个治疗相关的不良事件（TRAE），3例（6.0%）患者的TRAEs≥G3。最常见的TRAE（任何等级/等级≥3）是AST增加（18％/0％），蛋白尿（14%/2%），贫血（14%/2%），ALT升高(12%/0%)。未观察到明显的心脏毒性或出血。GFH018PK是线性和剂量非依赖性的，从5-85毫克，平均半衰期为2.25-8.60小时。9名患者(18.0%)病情稳定,一名胸腺癌患者实现了肿瘤缩小，最大靶病变减少18.4%。血清TGF-β1水平与临床反应无关。II期的综合推荐剂量定义为85mgBID14d-on/14d-off。
结论：GFH018单药治疗具有良好的安全性，无心脏毒性或出血。适度的疗效需要进一步的研究，包括组合策略。
背景：临床试验。gov(https://www.
结果：gov/)，NCT05051241。于2021-09-02注册。
方法：第一阶段，开放标签，多中心研究使用改良的3+3剂量递增和扩展设计。纳入患有未达到标准治疗的晚期实体瘤的成年患者。从5毫克开始，评估了高达85mg的8个剂量水平。患者在第1周期第1天单剂量后第4天开始接受GFH018BID(14d-开/14d-关)。随后的周期定义为28天。该研究还探讨了85mgBID7d-on/7d-off的安全性。使用NCI不良事件标准（NCI-CTCAEv5.0）对不良事件进行分级。使用非隔室方法分析PK。使用RECIST1.1评价疗效。收集血液样品用于生物标志物分析。
结果：50名患者被纳入并接受了至少一个剂量的GFH018。没有发生剂量限制性毒性，未达到最大耐受剂量。43例患者（86.0％）至少有一个治疗相关的不良事件（TRAE），3例（6.0%）患者的TRAEs≥G3。最常见的TRAE（任何等级/等级≥3）是AST增加（18％/0％），蛋白尿（14%/2%），贫血（14%/2%），ALT升高(12%/0%)。未观察到明显的心脏毒性或出血。GFH018PK是线性和剂量非依赖性的，从5-85毫克，平均半衰期为2.25-8.60小时。9名患者(18.0%)病情稳定,一名胸腺癌患者实现了肿瘤缩小，最大靶病变减少18.4%。血清TGF-β1水平与临床反应无关。II期的综合推荐剂量定义为85mgBID14d-on/14d-off。
结论：GFH018单药治疗具有良好的安全性，无心脏毒性或出血。适度的疗效需要进一步的研究，包括组合策略。
背景：临床试验。gov(https://www.
结果：gov/)，NCT05051241。于2021-09-02注册。
