{ "abstract": "Background/Objectives: Slow-flow vascular malformations, including venous malformation (VM), lymphatic malformation (LM), and Klippel–Trenaunay syndrome (KTS), are rare, symptomatic disorders with limited treatment options. This study evaluated the efficacy and safety of serabelisib, an orally available selective phosphoinositide 3-kinase α inhibitor, in these patients. Methods: This phase 3, multicenter, single-arm, confirmatory study was conducted in Japan (September 2023–June 2025). Patients aged ≥2 years received oral serabelisib once daily (100 mg for body weight ≥ 40 kg; 60 mg/m2 for <40 kg) for up to 52 weeks. The primary endpoint was the response rate at the final evaluation (≥24 weeks), defined as the proportion of patients achieving a ≥20% reduction from baseline in target lesion volume on blinded, centrally reviewed magnetic resonance imaging. The response rate was compared with a natural history-based null rate of 6.7% (exact binomial test). Trial registration: jRCT2041230064. Results: Thirty-six patients received serabelisib. The response rate was 30.6% (11/36; 95% confidence interval, 16.3–48.1%; p < 0.001) and remained significant in post hoc sensitivity analyses for null rates of up to 16%. Response rates were 19.0% (VM), 33.3% (LM), and 50.0% (KTS). Quality of life did not improve consistently. Adverse drug reactions (ADRs) occurred in 52.8% of patients (grade 3 or 4, 22.2%), most commonly hyperinsulinemia (13.9%), nausea (11.1%), and liver function test abnormal (11.1%); most hepatic ADRs (13 of 15 events) resolved after dose interruption or discontinuation. One death (tubulointerstitial nephritis) was judged unrelated to treatment. Conclusions: Serabelisib produced radiological responses exceeding a natural history benchmark in refractory VM, LM, and KTS, with hepatic toxicity requiring monitoring. Larger controlled studies with longer follow-up are needed to confirm its clinical benefit and long-term safety.", "abstract_shown": true, "affiliations": [ "Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan", "Department of Plastic Surgery, Tonan Hospital, Sapporo 060-0004, Japan", "Department of Radiology, Keio University School of Medicine, Tokyo 160-8582, Japan", "Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan", "Department of Plastic and Reconstructive Surgery, Yokohama City University School of Medicine, Yokohama 236-0004, Japan", "Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan", "Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan", "Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan", "Department of Plastic Surgery, National Hospital Organization Kobe Medical Center, Kobe 654-0155, Japan", "Department of Plastic Surgery, Fukuoka Children’s Hospital, Fukuoka 813-0017, Japan", "Department of Plastic and Reconstructive Surgery, Osaka Rosai Hospital, Sakai 591-8025, Japan", "Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA", "Kaken Pharmaceutical Co., Ltd., Tokyo 113-8650, Japan", "Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima 960-1295, Japan", "Department of Plastic Surgery, Tamaki Aozora Hospital, Tokushima 779-3125, Japan" ], "article_type": null, "arxiv": null, "author_total": 16, "authors": [ { "affs": [ 0 ], "name": "Noriko Aramaki-Hattori" }, { "affs": [ 1 ], "name": "Satoru Sasaki" }, { "affs": [ 1 ], "name": "Naoki Murao" }, { "affs": [ 2 ], "name": "Taiki Nozaki" }, { "affs": [ 3 ], "name": "Akihiro Fujino", "orcid": "0000-0003-2987-5081" }, { "affs": [ 4 ], "name": "Ayato Hayashi" }, { "affs": [ 5 ], "name": "Michio Ozeki" }, { "affs": [ 5 ], "name": "Saori Endo" }, { "affs": [ 6 ], "name": "Shimpei Akiyama" }, { "affs": [ 7, 8 ], "name": "Tadashi Nomura", "orcid": "0000-0002-0321-0770" }, { "affs": [ 7 ], "name": "Shunsuke Sakakibara", "orcid": "0000-0001-5644-4549" }, { "affs": [ 9, 10 ], "name": "Yoshihisa Kawakami", "orcid": "0000-0003-0780-8072" }, { "affs": [ 9 ], "name": "Ai Morita" }, { "affs": [ 11 ], "name": "Junko Ochi", "orcid": "0000-0001-9454-1219" }, { "affs": [ 12 ], "name": "Motoki Akamatsu", "orcid": "0009-0009-0521-4212" }, { "affs": [ 13, 14 ], "name": "Sadanori Akita", "orcid": "0000-0001-8225-9363" } ], "bibtex": "https://research.draconitic.com/paper/62dw66kh6j8q3.bib", "cited_by": 0, "doi": "10.3390/jcm15218624", "fulltext_url": null, "id": "62dw66kh6j8q3", "issns": [ "2077-0383" ], "landing_url": "https://www.mdpi.com/2077-0383/15/21/8624", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [], "openalex": null, "pdf_url": null, "pmcid": null, "pmid": null, "published": "2026-11-05", "publisher": "MDPI AG", "ris": "https://research.draconitic.com/paper/62dw66kh6j8q3.ris", "sources": [ { "first_seen": "2026-11-05T12:21:24Z", "native_id": "10.3390/jcm15218624", "source": "crossref", "url": "https://www.mdpi.com/2077-0383/15/21/8624" } ], "subjects": [ { "field": "medicine", "origin": "journal-openalex:F27", "subfield": "general" } ], "title": "Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison", "title_text": "Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison", "type": "peer-reviewed", "updated_at": "2026-11-07T00:21:23Z", "url": "https://research.draconitic.com/paper/62dw66kh6j8q3", "venue": "Journal of Clinical Medicine", "versions": [] }