Whitney Eng, Ionela Iacobas, Jonathan Perkins, Giuseppe Zampino, Chiara Leoni, Paola Sabrina Buonuomo, Alessandra Simonetti, Himanshu Goel, Michael Briones, Mo Huang, Gregory Goldmacher, Danny Liaw, Adrienne Hammill
{"title":"miransertib用于pik3ca相关过度生长谱或Proteus综合征患者的1/2期MOSAIC研究的安全性结果。","authors":"Whitney Eng, Ionela Iacobas, Jonathan Perkins, Giuseppe Zampino, Chiara Leoni, Paola Sabrina Buonuomo, Alessandra Simonetti, Himanshu Goel, Michael Briones, Mo Huang, Gregory Goldmacher, Danny Liaw, Adrienne Hammill","doi":"10.1186/s13023-025-03831-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>2</sup> every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m<sup>2</sup> 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"375"},"PeriodicalIF":3.5000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome.\",\"authors\":\"Whitney Eng, Ionela Iacobas, Jonathan Perkins, Giuseppe Zampino, Chiara Leoni, Paola Sabrina Buonuomo, Alessandra Simonetti, Himanshu Goel, Michael Briones, Mo Huang, Gregory Goldmacher, Danny Liaw, Adrienne Hammill\",\"doi\":\"10.1186/s13023-025-03831-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sup>2</sup> every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m<sup>2</sup> 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .</p>\",\"PeriodicalId\":19651,\"journal\":{\"name\":\"Orphanet Journal of Rare Diseases\",\"volume\":\"20 1\",\"pages\":\"375\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-07-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Orphanet Journal of Rare Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13023-025-03831-z\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Orphanet Journal of Rare Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13023-025-03831-z","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome.
Background: 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.
Methods: 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/m2 every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m2 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.
Results: 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.
Conclusion: 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.
Trial registration: NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .
期刊介绍：
Orphanet Journal of Rare Diseases is an open access, peer-reviewed journal that encompasses all aspects of rare diseases and orphan drugs. The journal publishes high-quality reviews on specific rare diseases. In addition, the journal may consider articles on clinical trial outcome reports, either positive or negative, and articles on public health issues in the field of rare diseases and orphan drugs. The journal does not accept case reports.
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