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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

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

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.