Eng Whitney, Iacobas Ionela, Perkins Jonathan, Zampino Giuseppe, Leoni Chiara, Buonuomo Paola Sabrina, Simonetti Alessandra, Goel Himanshu, Briones Michael, Huang Mo, Goldmacher Gregory, Liaw Danny, Hammill Adrienne
Boston Children's Hospital and the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Seattle Children's Hospital, 4800 Sandpoint Way NE, Seattle, WA, 98115, USA.
Orphanet J Rare Dis. 2025 Jul 25;20(1):375. doi: 10.1186/s13023-025-03831-z.
PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome are associated with mosaic tissue overgrowth of varying severity that commonly presents in childhood. The multicenter, open-label, phase 1/2 MOSAIC study (NCT03094832) was designed to evaluate the clinical efficacy and safety of the selective pan-AKT inhibitor miransertib for participants with PROS or Proteus syndrome.
Participants ≥ 2 years of age with PROS with documented somatic PIK3CA mutations or Proteus syndrome with documented somatic AKT1 mutations were enrolled to receive oral miransertib at a starting dose of 15 mg/m every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m every day thereafter, provided no clinically significant drug-related toxicities were observed. The initial primary objective of the study was to assess clinical response to miransertib. Due to study design and data collection limitations, evaluating efficacy was no longer considered feasible and the primary objective was updated in 2021 to evaluate the safety and tolerability of miransertib.
Between May 16, 2017 and January 25, 2021, 49 participants were enrolled and received ≥ 1 dose of study drug, comprising the safety analysis population. Forty-five participants had a diagnosis of PROS and four had a diagnosis of Proteus syndrome. The median (range) age at enrollment was 7 years (2-41). Median (range) duration of treatment was 20.5 months (9.9-45.6). A total of 23 (46.9%) participants had a drug-related adverse event, most commonly decreased neutrophil count (n = 6, 12.2%), increased blood insulin (n = 5, 10.2%), and stomatitis (n = 5, 10.2%). One (2.0%) participant experienced a grade 3 drug-related adverse event (deep vein thrombosis). No drug-related adverse events led to early study discontinuation or death. Laboratory assessment values remained generally stable throughout the study.
Miransertib was safe and tolerable in participants with a confirmed diagnosis of PROS or Proteus syndrome. Future investigations are needed to determine whether patients receive measurable clinical benefit from miransertib.
NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .
PIK3CA相关过度生长谱系（PROS）和普洛透斯综合征与不同严重程度的镶嵌组织过度生长有关，通常在儿童期出现。多中心、开放标签的1/2期MOSAIC研究（NCT03094832）旨在评估选择性泛AKT抑制剂米然色替对PROS或普洛透斯综合征患者的临床疗效和安全性。
纳入年龄≥2岁、患有记录在案的体细胞PIK3CA突变的PROS患者或患有记录在案的体细胞AKT1突变的普洛透斯综合征患者，接受口服米然色替，前3个周期（1个周期=28天）起始剂量为每天15mg/m²，此后每天25mg/m²，前提是未观察到临床上显著的药物相关毒性。该研究最初的主要目标是评估对米然色替的临床反应。由于研究设计和数据收集的限制，评估疗效不再被认为可行，2021年主要目标更新为评估米然色替的安全性和耐受性。
在2017年5月16日至2021年1月25日期间，49名参与者入组并接受了≥1剂研究药物，构成安全性分析人群。45名参与者被诊断为PROS，4名被诊断为普洛透斯综合征。入组时的中位（范围）年龄为7岁（2-41岁）。中位（范围）治疗持续时间为20.5个月（9.9-45.6个月）。共有23名（46.9%）参与者发生药物相关不良事件，最常见的是中性粒细胞计数减少（n=6，12.2%）、血液胰岛素升高（n=5，10.2%）和口腔炎（n=5，10.2%）。1名（2.0%）参与者发生3级药物相关不良事件（深静脉血栓形成）。没有药物相关不良事件导致研究提前终止或死亡。在整个研究过程中，实验室评估值总体保持稳定。
米然色替在确诊为PROS或普洛透斯综合征的参与者中是安全且可耐受的。需要进一步研究以确定患者是否能从米然色替中获得可衡量的临床益处。
NCT03094832，于2017年3月28日注册，https://clinicaltrials.gov/ct2/show/NCT03094832 。
