A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation

Purpose

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.

Conditions

  • PIK3CA-Related Overgrowth Spectrum (PROS)
  • Lymphatic Malformations
  • Vascular Malformations
  • PIK3CA Mutation
  • CLOVES Syndrome
  • Klippel Trenaunay Syndrome
  • Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)

Eligibility

Eligible Ages
Over 2 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • The participant must have a clinical diagnosis of PROS or a malformation within the ISSVA 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. Some participants may be eligible without a documented PIK3CA mutation as long as no other genetic driver has been documented. - 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.

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 or antibody within 5 half-lives of the therapy. 2. Local therapy including radiation, surgery, or other procedures within 28 days; lesion(s) must have demonstrated progression after the procedure.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Part 1: Dose selection: Participants ≥12 years old with PROS or malformations with PIK3CA mutation (Group 1) will be randomly assigned to a selected dose of RLY-2608 in an open-label fashion, stratified based on prior treatment with alpelisib. Groups 2 (6 to <12 years old) and 3 (2 to <6 years old): RLY-2608 will be studied in pediatric participants in a dose escalation design. Part 2: Part 2 will explore the clinical activity of RLY-2608 at 1 or more adult, adolescent, and pediatric recommended Phase 2 dose (RP2D) in various populations of participants with PROS and malformations associated with PIK3CA mutations in an open-label basket trial design. Part 3: In Part 3, adult (>18 yo), and adolescent and pediatric (6 to <18 yo) participants with PROS and malformations with PIK3CA mutation will be randomized to receive RLY-2608 at the Group 1 and 2 RP2Ds versus placebo. Randomization will be stratified based on indication, and prior systemic therapy.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Part 1, Group 1 		RLY-2608 for patients ≥12 years old with PROS or malformations with PIK3CA mutation. Multiple doses of RLY-2608 for oral administration.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 1, Group 2 		RLY-2608 for participants 6 to <12 years old with PROS or malformations with PIK3CA mutation. RLY-2608 will be studied in pediatric participants in a dose escalation design.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 1, Group 3 		Part 1, Group 3: RLY-2608 for participants 2 to <6 years old with PROS or malformations with PIK3CA mutation. RLY-2608 will be studied in pediatric participants in a dose escalation design.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 2, Group 1 		Dose expansion single-arm cohorts for various subpopulations of participants ≥12 years old with PROS or malformations with PIK3CA mutation. Oral dose of RLY-2608 as determined during Part 1.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 2, Group 2 		Dose expansion cohorts for participants 6 to <12 years old with PROS or malformations with PIK3CA mutation. Oral dose of RLY-2608 as determined during Part 1.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 2, Group 3 		Dose expansion cohorts for participants 2 to <6 years old with PROS or malformations with PIK3CA mutation. Oral dose of RLY-2608 as determined during Part 1.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Experimental
Part 3, Arm 1 		Adult (>18 yo), and adolescent and pediatric (6 to <18 yo) participants with PROS and malformations with PIK3CA mutation will be randomized to receive RLY-2608 at oral dose determined during Part 1/2 versus placebo.
  • Drug: RLY-2608
    RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
Placebo Comparator
Part 3, Arm 2 		Adult (>18 yo), and adolescent and pediatric (6 to <18 yo) participants with PROS and malformations with PIK3CA mutation will be randomized to receive placebo.
  • Drug: Placebo
    RLY-2608 matched-placebo

Recruiting Locations

Washington University in St. Louis and nearby locations

Washington University School of Medicine
St Louis 4407066, Missouri 4398678 63110
Contact:
Allison Barnwell
pedshemonctrialreferral@wustl.edu

More Details

NCT ID
NCT06789913
Status
Recruiting
Sponsor
Relay Therapeutics, Inc.

Study Contact

Relay Therapeutics, Inc
617-322-0731
ClinicalTrials@relaytx.com