Background and Significance: Lymphatic malformations(LyM) are rare, serious conditions, characterized by non-malignant masses consisting of fluid-filled cysts, resulting from an abnormal development of the lymphatic system. LyM impair quality of life through organ infiltration, pain, hemorrhage, infections, swelling, coagulopathy, inflammation, functional deficits, and anatomical distortion. Current treatments—surgery, sclerotherapy, embolization, and off-label medical therapy—have notable limitations, and no approved pharmacologic therapies exist. Most LyM cases (75%-80%) are driven by PIK3CA mutations, the gene encoding PI3Kα. Alpelisib (ALP), a PI3Kα-specific inhibitor, has accelerated approval in the US in PIK3CA-driven overgrowth spectrum (PROS), where LyM may occur as part of a broader syndrome. A previous study reported the shrinkage of LyM lesions following treatment with ALP in patients (pts) diagnosed with PROS. Preliminary evidence suggests that ALP may offer clinical benefit in pts with LyM, with manageable safety profiles and meaningful reductions in lesion size and associated symptoms. Despite this early evidence, no systematic, prospective randomized study has been conducted to evaluate ALP in pts with LyM harboring PIK3CA mutations. EPIK-L1 (NCT05948943) is a global, multicenter, double-blind, placebo-controlled study to assess the efficacy, safety, and pharmacokinetics (PK) of ALP in both pediatric and adult pts with PIK3CA-driven LyM.

Study Design and Methods: This is a seamless phase II/III study with 2 stages. Stage 1 aims to select the ALP dose(s) for Stage 2, based on a 24-week open-label core phase where pts are randomized in a 1:1 ratio to receive high- or low-dose ALP. Pts are assigned into 2 treatment groups: Group 1 (adults, ≥18 years) randomized 1:1 to receive a starting dose of 125 mg or 250 mg; Group 2 (pediatric pts aged 6-17 years) randomized 1:1 to receive 50 mg or 125 mg dose. The Stage 1 core phase is followed by an extension phase which allows individualized dose escalation to optimize response. Stage 2 aims to evaluate the efficacy and safety profile at the selected dose(s) of ALP and comprises a 24-week 2:1 randomized, double-blind, placebo-controlled period, where pts are assigned into 2 treatment groups based on age: Group 3 (adults, ≥18 years), Group 4 (pediatric pts aged 6-17 years), followed by an open-label extension phase. Additionally, a parallel open-label 24-week phase will be conducted for Group 5 (pediatric pts aged 0-5 years), followed by an open-label extension phase. The primary objective is to demonstrate the efficacy of ALP in at least one of the two groups, based on the radiological response (≥20% reduction from baseline in the sum of target lesion volumes, assessed by MRI by a Blinded Independent Review Committee [BIRC]) at the 24-week of Stage 2. Secondary endpoints include Patient Global Impression of Severity (PGI-S) score (≥1-point improvement compared to baseline based on PGI-S scale; key objective), safety, tolerability, duration of response, PK, and frequency of LyM-related symptoms/complications at the 24-week visit and over time.

Eligible pts have a physician-confirmed and documented diagnosis of LyM (excluding those meeting PROS criteria); confirmation of somatic PIK3CA mutation(s); ≥1 measurable LyM lesion confirmed by a BIRC; Karnofsky/Lansky performance status index ≥50 within 7 days before start of study treatment, PGI-S score of mild, moderate, severe, or very severe at screening; and the provision of signed informed consent/assent and willingness to comply with study requirements. Pts must be either ineligible for or unwilling to undergo non-drug therapies (sclerotherapy, embolization, surgery) before week 24 of either study stage and must be able to ingest the study drug in its required form, including via feeding tube if necessary. Key exclusion criteria include pts with physician-confirmed diagnosis of PROS, central conducting lymphatic anomaly, generalized lymphatic anomaly, Gorham-Stout disease, or Kaposiform lymphangiomatosis; with a history of Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, or a diagnosis of type I diabetes mellitus or uncontrolled type II diabetes; prior treatment with ALP or other PI3K inhibitors lasting ≥2 weeks.

Stage 1 enrollment (Groups 1 and 2 = 21 each) has been completed. The study now aims to enroll approximately 192 pts in Stage 2 (Groups 3 and 4 = 90 each, Group 5 = ~12).

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2025
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