Background and Significance: PROS is a group of rare clinical syndromes caused by tissue-specific somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene, which lead to the activation of the AKT and mTOR signaling pathways, thereby resulting in tissue growth in areas such as adipose tissue, muscle, skin, bone, blood or lymphatic vessels, and neural tissue. Currently, there is no cure for PROS. Treatment options include invasive procedures and surgeries, which are rarely curative. Alpelisib (ALP), a small-molecule PI3Kα-specific inhibitor, received accelerated approval from the FDA for patients aged ≥2 years with severe PROS manifestations, based on data from patients (pts) treated under a compassionate use program. EPIK-P4 (NCT06997588) is an open-label, phase II, single arm, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of ALP in pediatric and adult patients with PROS, regardless of disease severity. EPIK-P4 will evaluate a different dosing regimen compared to the prior prospective phase II study, EPIK-P2.

Study Design and Methods: This study comprises a 48-week Core period, a 120-week Extension 1 period, and an Extension 2 period with assessments every 24 weeks until the last participant completes Extension 1. Participants are assigned to 2 treatment groups based on age: Group 1 comprising adults (≥18 yrs) receiving a starting dose of 250-mg ALP orally once daily, and Group 2 including pediatric participants (2-17 yrs) receiving a starting dose of 50 mg (2-5 yrs) or 125 mg (6-17 yrs) orally once daily, with the option for dose escalation.Key inclusion criteria include participants aged ≥2 yrs with a diagnosis of PROS, symptomatic and progressive overgrowth, confirmed somatic PIK3CA variant, Karnofsky or Lansky performance status index ≥50, Patient Global Impression of Severity (PGI-S) score of mild to very severe, adequate bone marrow and organ function, and at least one measurable PROS-related lesion (≥2 cm) confirmed by a Blinded Independent Review Committee (BIRC) with associated symptoms or functional limitations. Key exclusion criteria include participants with only isolated macrodactyly, epidermal nevus, and/or macrocephaly without other PROS-related lesions; prior treatment with ALP or other PI3K inhibitors (except short-term attempts <2 weeks stopped ≥4 weeks prior); major surgery within 3 months; radiation for PROS within 12 months; clinically meaningful thrombotic events or sclerotherapy/embolization within 30 or 42 days, respectively; clinically meaningful bleeding from PROS lesions within 30 days; or worsening PROS-related laboratory abnormalities, symptoms, or signs indicating uncontrolled disease during screening. The study aims to enroll approximately 104 participants (52 per group). The primary objective is to demonstrate the efficacy of ALP in at least one of the two groups, based on the proportion of participants achieving a ≥20% reduction from baseline in the sum of target lesion volumes, as confirmed by magnetic resonance imaging (MRI) by a Blinded Independent Review Committee (BIRC), with no individual target lesion increasing ≥20% from nadir, without progression of non-target lesions, and without the appearance of new lesions. Secondary objectives include evaluating the efficacy, safety, PK, and tolerability of ALP in adult and pediatric participants with PROS by assessing changes in lesions, symptoms, complications, healthcare utilization, patient-reported outcomes, duration of response, time to treatment failure, and overall clinical response at scheduled protocol defined time points. The first patient first visit is planned for October 2025.

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2025
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