Targeted oncology · 2025
Phase 1 Study of Luvometinib Use in Pediatric Patients with Neurofibromatosis Type 1-Related Unresectable Plexiform Neurofibromas.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Hu Xiaojie, Wu Zhuli, Wang Jinhu, Li Wenbin, Zeng Kang, Li Yanling, Tao Juan, Guan Zhonghai, Kang Zhuang, Xu Zhongyuan, Ma Yaohui, Yang Liu, Wang Xingli, Han Pu, Lin Hongmei, Diao Lei, Tan Yan, Zhong Wen, Hui Ai-Min, Li Changxing, Lin Xiaoxi
Аннотация
BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by plexiform neurofibromas (PNs), which are present in 20-60% of NF1 and may cause potentially life-threatening complications. Complete surgical resection of these PNs is generally not feasible, and regrowth after incomplete surgical resection has been observed. Luvometinib is a novel, oral, highly potent selective MEK1/2 inhibitor that has shown activity in adult NF1-related PN.
OBJECTIVE: To evaluate the safety and preliminary efficacy of luvometinib in a phase 1 trial in pediatric patients with NF1-related PN.
PATIENTS AND METHODS: This multicenter, single-arm, phase 1 study included pediatric patients (2-18 years old) with unresectable NF1-related PN. Patients received luvometinib orally once daily in 28-day cycles until progression or unacceptable toxicity, using a population pharmacokinetics model-informed approach to identify the starting dose of 4 mg/m2. Primary endpoints were dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D). Tumor response was a secondary endpoint.
RESULTS: In total, 19 patients were enrolled; 10 at 4 mg/m2 and 9 at 5 mg/m2. Median age was 10.0 years (range 5-17). No DLTs were reported. The maximum tolerated dose (MTD) was not reached; the RP2D was 5 mg/m2. The most common treatment-related adverse events (TRAEs) were paronychia (52.6%) and mouth ulceration (42.1%), with a single grade ≥ 3 TRAE reported for each: paronychia (5.3%), prolonged QT on electrocardiogram (5.3%), and ingrown nail (5.3%). There was one discontinuation owing to a treatment-related serious AE (SAE) of rhabdomyolysis, the only treatment-related SAE. Within the 5 mg/m2 group, six out of nine patients (66.7%) had a confirmed response; within the 4 mg/m2 group, none did. Among patients with tumor pain (numerical rating scale [NRS] ≥ 2) at baseline and at least one post-baseline measurement, 2/3 (66.7%) reported an improvement of ≥ 2 points in the 4 mg/m2 dose group and 3/3 (100.0%) in the 5 mg/m2 dose group.
CONCLUSIONS: Luvometinib had a manageable safety profile in pediatric patients with unresectable NF1-related PN. Encouraging preliminary efficacy was observed, particularly among patients receiving the RP2D of 5 mg/m2, supporting further investigation of luvometinib in this setting.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT04954001 (first posted: 8 July 2021).
OBJECTIVE: To evaluate the safety and preliminary efficacy of luvometinib in a phase 1 trial in pediatric patients with NF1-related PN.
PATIENTS AND METHODS: This multicenter, single-arm, phase 1 study included pediatric patients (2-18 years old) with unresectable NF1-related PN. Patients received luvometinib orally once daily in 28-day cycles until progression or unacceptable toxicity, using a population pharmacokinetics model-informed approach to identify the starting dose of 4 mg/m2. Primary endpoints were dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D). Tumor response was a secondary endpoint.
RESULTS: In total, 19 patients were enrolled; 10 at 4 mg/m2 and 9 at 5 mg/m2. Median age was 10.0 years (range 5-17). No DLTs were reported. The maximum tolerated dose (MTD) was not reached; the RP2D was 5 mg/m2. The most common treatment-related adverse events (TRAEs) were paronychia (52.6%) and mouth ulceration (42.1%), with a single grade ≥ 3 TRAE reported for each: paronychia (5.3%), prolonged QT on electrocardiogram (5.3%), and ingrown nail (5.3%). There was one discontinuation owing to a treatment-related serious AE (SAE) of rhabdomyolysis, the only treatment-related SAE. Within the 5 mg/m2 group, six out of nine patients (66.7%) had a confirmed response; within the 4 mg/m2 group, none did. Among patients with tumor pain (numerical rating scale [NRS] ≥ 2) at baseline and at least one post-baseline measurement, 2/3 (66.7%) reported an improvement of ≥ 2 points in the 4 mg/m2 dose group and 3/3 (100.0%) in the 5 mg/m2 dose group.
CONCLUSIONS: Luvometinib had a manageable safety profile in pediatric patients with unresectable NF1-related PN. Encouraging preliminary efficacy was observed, particularly among patients receiving the RP2D of 5 mg/m2, supporting further investigation of luvometinib in this setting.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT04954001 (first posted: 8 July 2021).