Purpose:To determine to the activity and safety of TGF-β inhibitor, vactosertib in combination with imatinib in patients with desmoid tumors. Patients and Methods: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amendable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. Results:No dose-limiting toxicities were observed during the phase Ib, therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. The most toxicities were mild to moderate myalgia (n=10, 37%), anemia (n=10, 37%), and nausea (n=9, 33.3%). Common grade 3-4 toxicities included neutropenia (n=6, 22.2%) and anemia (n=5, 18.5%). Conclusions: Vactosertib and imatinib combination was well-tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-β inhibitor, in this rare and difficult-to-treat desmoid tumor.

中文翻译：

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转化生长因子-β 抑制剂 vactosertib 联合伊马替尼治疗硬纤维瘤的临床活性：一项多中心 Ib/II 期研究

目的：确定 TGF-β 抑制剂 vactosertib 联合伊马替尼治疗硬纤维瘤患者的活性和安全性。患者和方法：在这项研究者发起的、开放标签、多中心、Ib/II 期试验中，纳入了无法接受局部治疗（手术和/或放疗）的硬纤维瘤患者或至少一次治疗后疾病进展的患者。参与者每 28 天每天服用 400 毫克伊马替尼联合 vactosertib（服用 5 天，休息 2 天，每天两次）。在Ib期中，vactosertib剂量设定为100 mg（水平-1）和200 mg（水平1）以确定推荐的II期剂量（RP2D）。II 期评估了疗效，主要终点是 16 周时的无进展率 (PFR)。结果：在 Ib 期未观察到剂量限制性毒性，因此 RP2D 的剂量被定义为每天 400 mg 伊马替尼联合 200 mg vactosertib。在接受评估的 27 名患者中，7 名 (25.9%) 获得了确认的部分缓解，19 名 (70.4%) 病情稳定。16 周和 1 年时的 PFR 分别为 96.3% 和 81.0%。最严重的毒性是轻度至中度肌痛（n=10，37%）、贫血（n=10，37%）和恶心（n=9，33.3%）。常见的 3-4 级毒性包括中性粒细胞减少症 (n=6, 22.2%) 和贫血 (n=5, 18.5%)。结论：Vactosertib 和伊马替尼联合用药耐受性良好，在进展性局部晚期硬纤维瘤患者中具有良好的临床活性。这是第一项针对这种罕见且难以治疗的硬纤维瘤研究新型靶标药物 TGF-β 抑制剂的研究。