Sirolimus in Patients with Overgrowth, with or without Vascular Malformations: The SIPA-SOS Study

Abstract

BackgroundLocalized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component.

ObjectiveTo evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period.

MethodsWe conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety.

ResultsNo patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [≥]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion.

ConclusionsSirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.

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BibTeX RIS

BibTeX

@misc{cericola2026sirolimus,
  title = {{Sirolimus in Patients with Overgrowth, with or without Vascular Malformations: The SIPA-SOS Study}},
  author = {G. Cericola and B. Haeberle and J. Haehl and S. berg and S. Leschka and s. grueninger and c. schmoor and S. wirtz and A. Holm and c. m. niemeyer and A. Puzik and M. Zenker and M. Wildgruber and j. roessler and F. G. Kapp},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.25.26364046},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.25.26364046v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Sirolimus in Patients with Overgrowth, with or without Vascular Malformations: The SIPA-SOS Study
AU  - G. Cericola
AU  - B. Haeberle
AU  - J. Haehl
AU  - S. berg
AU  - S. Leschka
AU  - s. grueninger
AU  - c. schmoor
AU  - S. wirtz
AU  - A. Holm
AU  - c. m. niemeyer
AU  - A. Puzik
AU  - M. Zenker
AU  - M. Wildgruber
AU  - j. roessler
AU  - F. G. Kapp
PY  - 2026
DA  - 2026/09/25
PB  - medRxiv
DO  - 10.64898/2026.09.25.26364046
UR  - https://www.medrxiv.org/content/10.64898/2026.09.25.26364046v1
AB  - BackgroundLocalized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component.  ObjectiveTo evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period.  MethodsWe conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety.  ResultsNo patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [≥]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion.  ConclusionsSirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.
ER  -

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