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 C 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.