EPIK-P2: A prospective phase 2, double-blind, randomized, placebo-controlled study of alpelisib in pediatric and adult patients (Pts) with PIK3CA-related overgrowth spectrum (PROS).
Authors: Canaud Guillaume , López Gutiérrez Juan Carlos , Hammill Adrienne M. , Weibel Lisa , Vincent Ghislaine , Niglis Séverine , Paul Michaela , Adams Denise M. 
Published: June 2021

TPS3160 Background: Somatic gain-of-function mutations in the PIK3CA gene, encoding the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic α subunit (p110α), can result in PI3K pathway hyperactivation. PROS is an umbrella term for rare, phenotypically varied, but overlapping features driven by PIK3CA mutations. Disease onset is often congenital or in early childhood; presentation ranges widely from localized overgrowth to pleiotropic, severe overgrowth. Complications depend on anatomical site and extent of overgrowth. Management of PROS currently involves symptomatic treatment of its manifestations; an unmet need exists for targeted, systemic therapies. Alpelisib, a PI3Kα inhibitor, has demonstrated encouraging clinical observations and a promising safety profile; after 6 mo of treatment, pediatric and adult pts with PROS experienced improvements in symptoms without requiring surgery. A low rate of side effects was observed (Venot Q, et al. Nature. 2018;558:540-6). Methods: EPIK-P2 is a prospective, phase 2, multicenter study with an upfront 16-week, randomized, double-blind, placebo-controlled period. Key eligibility criteria include male or female ≥6 yr of age with PROS and symptomatic and/or progressive overgrowth; ≥1 PROS-related measurable lesion confirmed by a Blinded Independent Review Committee (BIRC) and documented somatic PIK3CA mutation. Pts with isolated cases of macrodactyly, epidermal nevus/nevi, or macrocephaly in absence of other PROS-related lesions; previous treatment with PI3K inhibitor(s); or debulking surgery within 3 mo are not eligible. Approximately 138 pts will be enrolled into 2 groups comprising adult (age ≥18 yr) and pediatric (ages 6-17 yr) pts. Pts will be randomized 2:1 to daily oral alpelisib or matching placebo; adults will receive 125 mg and pediatric pts 50 mg. After 16 weeks, pts randomized to placebo will switch to alpelisib in a blinded fashion; pts receiving alpelisib will continue alpelisib. Treatment will continue for up to 5 yr. The primary objective is to demonstrate the efficacy of alpelisib by the proportion of pts randomized to alpelisib with a response at Week 24 in each group. Response is defined as ≥20% volume reduction in the symptomatic target lesion(s) per BIRC. The key secondary objective is to demonstrate efficacy of alpelisib vs placebo based on the proportion of pts in each group with response at Week 16. Other secondary outcomes include safety and tolerability, duration of response, overall clinical response rates, changes in symptoms and comorbidities, patient-reported outcomes, pharmacokinetics, and healthcare utilization. An exploratory group of pts (n = 12) ages 2-5 yr will be later enrolled once a starting dose of alpelisib is confirmed in these pts. Enrollment of 150 pts is anticipated. Clinical trial information: NCT04589650.