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

Phase 2

Recruiting

• Conditions: PIK3CA-Related Overgrowth Spectrum (PROS); Lymphatic Malformations; Vascular Malformations; PIK3CA Mutation; CLOVES Syndrome; Klippel Trenaunay Syndrome; Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)
• Interventions: Drug: RLY-2608; Drug: Placebo

• Registration Number: NCT06789913
• Lead Sponsor: Relay Therapeutics, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-01-17
• Study First Submitted QC: 2025-01-17
• Study First Posted: 2025-01-23
• Status Verified: 2025-04
• Study Start: 2025-04
• Last Update Submitted: 2025-04-17
• Last Update Posted: 2025-04-23
• Primary Completion: 2031-07
• Study Completion: 2031-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 280

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1, Group 1	RLY-2608	RLY-2608 for patients ≥12 years old with PROS or malformations with PIK3CA mutation. Multiple doses of RLY-2608 for oral administration.
Part 1, Group 2	RLY-2608	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.
Part 1, Group 3	RLY-2608	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.
Part 2, Group 1	RLY-2608	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.
Part 2, Group 2	RLY-2608	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.
Part 2, Group 3	RLY-2608	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.
Part 3, Arm 1	RLY-2608	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.
Part 3, Arm 2	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3	Cycle 1 (4-week cycle) of treatment and at the end of every cycle (4-week cycles) until study discontinuation
Parts 1 and 2: Occurrence/frequency of Adverse Events (AEs), changes in vital signs, ECGs, and safety laboratory tests and their relationship to the study drugs (safety and tolerability).	Cycle 1 (4-week cycle) of treatment and at the end of every cycle (4-week cycles) until study discontinuation
Part 3: Percentage of participants with volumetric Response.	Baseline, Week 24

Secondary Outcome Measures

Name	Time	Method
Part 3: Change from baseline in EQ-5D-5L, EQ-5D-Y-3L, or EQ-5D-Y-3L Proxy 1	Approximately once a month until end of treatment
Part 3: Percent change from baseline in lesion volume	Approximately every 3 months for approximately the first year, and then every 6 months during treatment
Part 1 and 2: Percent change from baseline in lesion volume	Baseline, Week 24
Part 1 and 2: Duration of response, defined as the time of first documented response to the date of first documented disease progression or death due to any cause	Approximately every 3 months for approximately the first year, and then every 6 months during treatment
Part 1 and 2: Percentage of participants with volumetric response	Baseline, week 12, week 24
Part 1 and 2: Plasma concentrations and PK parameters of RLY-2608	Approximately every 2 weeks in Cycle 1 (4-week cycle), then again at Cycle 4 and Cycle 7
Part 1 and 2: PIK3CA mutational status in lesional fluid and/or tissue	Prior to enrollment
Part 3: Percentage of participants with improvement compared to baseline based on PGI-S, PGI-C and IGIC	Approximately once a month until end of treatment
Part 3: Change from baseline by age-appropriate PROMIS Profile	Approximately once a month until end of treatment

Trial Locations

Locations (1)

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States