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Background <p>In patients with slow-flow vascular malformations (SFVMs) including venous malformations (VM), lymphatic malformations (LM) or Klippel–Trenaunay Syndrome (KTS), somatic gain-of-function mutations in genes encoding phosphatidyl inositol 3-kinase alpha (PI3Kα, gene name <i>PIK3CA</i>) have been identified. A phase 2 study was conducted with the patients to assess the efficacy and safety of ART-001 (serabelisib), an orally available selective PI3Kα inhibitor.</p> Methods <p>This is a multicenter, randomized, double-blind, proof-of-concept, phase 2 trial. Eligible participants were patients aged 2&#xa0;years and older, diagnosed either with VM, LM or KTS. Participants were administered either 50 or 100&#xa0;mg of ART-001 for 24&#xa0;weeks. The primary endpoint was the response rate defined as the proportion of participants who achieved ≥ 20% reduction in lesion volume at week 24. Secondary endpoints include safety, pharmacokinetics, pain, and quality of life scores.</p> Results <p>Thirty-five patients (median age: 14&#xa0;years old; VM, n = 17, KTS, n = 13 and LM, n = 5) were randomly assigned and received treatment (50&#xa0;mg, n = 17 and 100&#xa0;mg, n = 18). ART-001 showed a response rate: 29.4% (95% confidence interval 10.3–56.0%) at 50&#xa0;mg and 33.3% (13.3–59.0%) at 100&#xa0;mg. Mean lesion volume reductions at 50&#xa0;mg and 100&#xa0;mg were −&#xa0;2.3% (95% CI −&#xa0;14.3 to 9.6%) and −&#xa0;12.6% (−&#xa0;25.3 to 0.06%), respectively. No drug-related serious adverse events were observed. Treatment-emergent adverse events were generally mild to moderate and transient. Pharmacokinetic profiles were similar between pediatric and adolescent/adult patients except for lower C<sub>trough</sub> levels in pediatric patients.</p> Conclusion <p>ART-001 was effective and well-tolerated in patients with SFVMs. These results support the further development of ART-001 in SFVMs and other PIK3CA-related overgrowth syndromes to confirm clinical benefits and long-term safety.</p> <p><i>Trial registration</i>:&#xa0;Japan Registry of Clinical Trial, jRCT2071210027. Registered May 25 2021,<a href="https://jrct.niph.go.jp/en-latest-detail/jRCT2071210027">https://jrct.niph.go.jp/en-latest-detail/jRCT2071210027</a></p>

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A phase 2 randomized, double-blind trial of ART-001, a selective PI3Kα inhibitor, for the treatment of slow-flow vascular malformations

  • 期刊论文

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  • 发表日期：

    2025年2月10日

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  • Michio Ozeki,
  • Akira Tanaka,
  • Kanako Kuniyeda,
  • Taiki Nozaki,
  • Akihiro Fujino,
  • Tadashi Nomura,
  • Naoto Uemura,
  • Souichi Suenobu,
  • Noriko Aramaki-Hattori,
  • Ayato Hayashi,
  • Aiko Kato,
  • Hiro Kiyosue,
  • Kotaro Imagawa,
  • Munetomo Nagao,
  • Fumiaki Shimizu,
  • Junko Ochi,
  • Saya Horiuchi,
  • Tetsuji Ohyama,
  • Haruhi Ando,
  • Hiroshi Nagabukuro

摘要

Background

In patients with slow-flow vascular malformations (SFVMs) including venous malformations (VM), lymphatic malformations (LM) or Klippel–Trenaunay Syndrome (KTS), somatic gain-of-function mutations in genes encoding phosphatidyl inositol 3-kinase alpha (PI3Kα, gene name PIK3CA) have been identified. A phase 2 study was conducted with the patients to assess the efficacy and safety of ART-001 (serabelisib), an orally available selective PI3Kα inhibitor.

Methods

This is a multicenter, randomized, double-blind, proof-of-concept, phase 2 trial. Eligible participants were patients aged 2 years and older, diagnosed either with VM, LM or KTS. Participants were administered either 50 or 100 mg of ART-001 for 24 weeks. The primary endpoint was the response rate defined as the proportion of participants who achieved ≥ 20% reduction in lesion volume at week 24. Secondary endpoints include safety, pharmacokinetics, pain, and quality of life scores.

Results

Thirty-five patients (median age: 14 years old; VM, n = 17, KTS, n = 13 and LM, n = 5) were randomly assigned and received treatment (50 mg, n = 17 and 100 mg, n = 18). ART-001 showed a response rate: 29.4% (95% confidence interval 10.3–56.0%) at 50 mg and 33.3% (13.3–59.0%) at 100 mg. Mean lesion volume reductions at 50 mg and 100 mg were − 2.3% (95% CI − 14.3 to 9.6%) and − 12.6% (− 25.3 to 0.06%), respectively. No drug-related serious adverse events were observed. Treatment-emergent adverse events were generally mild to moderate and transient. Pharmacokinetic profiles were similar between pediatric and adolescent/adult patients except for lower Ctrough levels in pediatric patients.

Conclusion

ART-001 was effective and well-tolerated in patients with SFVMs. These results support the further development of ART-001 in SFVMs and other PIK3CA-related overgrowth syndromes to confirm clinical benefits and long-term safety.

Trial registration: Japan Registry of Clinical Trial, jRCT2071210027. Registered May 25 2021,https://jrct.niph.go.jp/en-latest-detail/jRCT2071210027