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

April 30, 2026 updated by: Relay Therapeutics, Inc.
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

277

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
    • New South Wales
      • Randwick, New South Wales, Australia, 2031
    • Queensland
      • South Brisbane, Queensland, Australia, 4101
    • Victoria
      • Clayton, Victoria, Australia, 3168
      • Parkville, Victoria, Australia, 3050
      • Parkville, Victoria, Australia, 3052
  • Belgium
  • Germany
      • Halle, Germany, Germany
  • Italy
      • Roma, Italy
        • Recruiting
        • Ospedale Pediatrico Bambino Gesù IRCCS
        • Contact:
      • Torino, Italy
        • Recruiting
        • A.O.U Città della Salute e della Scienza di Torino
        • Contact:
  • Spain
  • United Kingdom
      • London, United Kingdom
        • Recruiting
        • Great Ormond Street Hospital for Children
        • Contact:
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85016
    • Arkansas
      • Little Rock, Arkansas, United States, 72202
        • Recruiting
        • Arkansas Children's Hospital
        • Contact:
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University of California, Los Angeles
        • Contact:
      • Palo Alto, California, United States, 94304
        • Recruiting
        • Stanford University
        • Contact:
      • San Francisco, California, United States, 94158
    • Colorado
      • Aurora, Colorado, United States, 80045
    • Georgia
      • Atlanta, Georgia, United States, 30329
    • Indiana
      • Indianapolis, Indiana, United States, 46202
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Recruiting
        • Johns Hopkins Medical Institute
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
    • Michigan
    • Minnesota
      • Rochester, Minnesota, United States, 55905
    • Missouri
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Recruiting
        • UNC Chapel Hill
        • Contact:
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital Medical Center
        • Contact:
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic Children's
        • Contact:
    • Texas
      • Houston, Texas, United States, 77030
    • Washington
      • Seattle, Washington, United States, 98101
    • Wisconsin
      • Madison, Wisconsin, United States, 53715

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Key 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.

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 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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Part 3: Percentage of participants with volumetric Response.
Time Frame: Baseline, Week 24
Baseline, Week 24
Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3
Time Frame: Cycle 1 of treatment and at the end of every cycle until study discontinuation
Cycle 1 of treatment and at the end of every cycle 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).
Time Frame: Cycle 1 of treatment and at the end of every cycle until study discontinuation
Cycle 1 of treatment and at the end of every cycle until study discontinuation

Secondary Outcome Measures

Outcome Measure
Time Frame
Part 1 and 2: Percent change from baseline in lesion volume
Time Frame: Baseline, Week 24
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
Time Frame: Approximately every 3 months for approximately the first year, and then every 6 months during treatment
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
Time Frame: Baseline, week 12, week 24
Baseline, week 12, week 24
Part 1 and 2: PIK3CA mutational status in lesional fluid and/or tissue
Time Frame: Prior to enrollment
Prior to enrollment
Part 3: Percentage of participants with improvement compared to baseline based on PGI-S, PGI-C and IGIC
Time Frame: Approximately once a month until end of treatment
Approximately once a month until end of treatment
Part 3: Change from baseline by age-appropriate PROMIS Profile
Time Frame: Approximately once a month until end of treatment
Approximately once a month until end of treatment
Part 3: Percent change from baseline in lesion volume
Time Frame: Approximately every 3 months for approximately the first year, and then every 6 months during treatment
Approximately every 3 months for approximately the first year, and then every 6 months during treatment
Part 1 and 2: Plasma concentrations and PK parameters of RLY-2608
Time Frame: Approximately every 2 weeks in Cycle 1, then again at Cycles 2, 4 and Cycle 7 depending on the participant's group
Approximately every 2 weeks in Cycle 1, then again at Cycles 2, 4 and Cycle 7 depending on the participant's group
Part 3: Change from baseline in EQ-5D, EQ-5D-Y, or EQ-5D-Y Proxy
Time Frame: Approximately once a month until end of treatment
Approximately once a month until end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Relay Therapeutics, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 13, 2025

Primary Completion (Estimated)

July 1, 2031

Study Completion (Estimated)

October 1, 2031

Study Registration Dates

First Submitted

January 17, 2025

First Submitted That Met QC Criteria

January 17, 2025

First Posted (Actual)

January 23, 2025

Study Record Updates

Last Update Posted (Actual)

May 5, 2026

Last Update Submitted That Met QC Criteria

April 30, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RLY-2608-201
  • 2024-518895-30-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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