Overview

This is a 3-part Phase 2 randomized study evaluating the safety and efficacy of the mutant-selective PI3Kα inhibitor, RLY-2608, in adults and children with PIK3CA Related Overgrowth Spectrum (PROS) and malformations driven by PIK3CA mutation. Part 1 is a dose selection, Part 2 is a basket design with exploratory single-arm cohorts for various subpopulations of participants, and Part 3 is randomized, double-blinded study vs placebo.

Eligibility

Key Inclusion Criteria:

• The participant must have a clinical diagnosis of PROS or a malformation within the ISSVA 2018 classification.
• One or more documented activating PIK3CA mutation(s) that are targeted by selective PI3Kα inhibitors in lesional tissue and/or cell-free DNA from the lesion or blood
• Lansky (<16 yo) or Karnofsky (≥16 yo) performance status of ≥50.
• Agree to provide archived lesional fluid and/or tissue or be willing to undergo pretreatment lesional biopsy (if considered safe and medically feasible) to assess PIK3CA status.

Key Exclusion Criteria:

• History of hypersensitivity to PI3K inhibitors.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
• Clinically significant, uncontrolled cardiovascular disease
• Received disease-directed therapy prior to the first dose of study drug:
  1. Systemic therapy within 5 half-lives of the drug or 14 days, whichever is longer and received antibody therapy within 28 days.
  2. Local therapy including radiation, surgery, or other procedures within 28 days; lesion(s) must have demonstrated progression after the procedure.