Purpose

PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients.

Methods

Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes.

Results

Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement).

Conclusion

Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

中文翻译：

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低剂量 PI3K 抑制剂 taselisib 在成年 CLOVES 和 Klippel-Trenaunay 综合征 (KTS) 患者中的安全性和有效性：TOTEM 试验，1/2 期多中心、开放标签、单臂研究

目的

PIK3CA相关过度生长谱 (PROS) 中的 PIK3CA 致病变异激活磷酸肌醇 3-激酶信号传导，为靶向治疗提供了基本原理，但没有药物在该人群中证明有效和安全。我们的目标是确定低剂量 taselisib（一种选择性 I 类 PI3K 抑制剂）在 PROS 患者中的六个月耐受性和有效性。

方法

患有 PROS 和PIK3CA致病性变异的 16 岁以上患者被纳入一项 IB/IIA 期多中心、开放标签单臂试验（6 名患者 1 mg/天 taselisib，然后 24 名 2 mg/天）。主要结果是剂量限制毒性（DLT）的发生。疗效结果是治疗后（1）受累和未受累部位的组织体积在临床和影像学上的相对变化；(2) 相关的皮肤血管结果；(3) 生物学参数；(4) 生活质量；(5) 患者报告的结果。

结果

在 19 名入组患者中，2 名患有 DLT（肠炎和硬脑膜炎）导致试验提前终止（17 名接受治疗，10 名完成研究）。1 mg 队列（ n  = 6）未发生严重不良反应。未观察到受影响的组织体积显着减少（平均 -4.2%；p  = 0.81；SD 14.01）。13 名 (76.4%) 参与者报告了临床改善（疼痛减轻、慢性出血消退、功能改善）。

结论

尽管功能有所改善，但低剂量 taselisib 的安全性使其无法长期使用。