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

NCT06789913 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: RLY-2608-2012024-518895-30-00
• Study Type: interventional
• Target: 277
• Locations: 7 countries
• Sites: 31

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.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3

  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).

  Cycle 1 of treatment and at the end of every cycle until study discontinuation

• Part 3: Percentage of participants with volumetric Response.

  Baseline, Week 24

Secondary Outcomes (9)

• 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, then again at Cycles 2, 4 and Cycle 7 depending on the participant's group

• Part 1 and 2: PIK3CA mutational status in lesional fluid and/or tissue

  Prior to enrollment

Study Arms (8)

Part 1, Group 1

EXPERIMENTAL

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

Part 1, Group 2

EXPERIMENTAL

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

Part 1, Group 3

EXPERIMENTAL

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

Part 2, Group 1

EXPERIMENTAL

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

Part 2, Group 2

EXPERIMENTAL

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

Part 2, Group 3

EXPERIMENTAL

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

Part 3, Arm 1

EXPERIMENTAL

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

Part 3, Arm 2

PLACEBO COMPARATOR

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

Interventions

RLY-2608 DRUG

RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.

Part 1, Group 1; Part 1, Group 2; Part 1, Group 3; Part 2, Group 1; Part 2, Group 2; Part 2, Group 3; Part 3, Arm 1

Placebo DRUG

RLY-2608 matched-placebo

Part 3, Arm 2

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Relay Therapeutics, Inc.: lead

Study Sites (31)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

RECRUITING

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

RECRUITING

University of California, Los Angeles

Los Angeles, California, 90095, United States

RECRUITING

Stanford University

Palo Alto, California, 94304, United States

RECRUITING

University of California, San Francisco

San Francisco, California, 94158, United States

RECRUITING

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

RECRUITING

Children's Hospital of Atlanta

Atlanta, Georgia, 30329, United States

RECRUITING

Riley Children's Hospital

Indianapolis, Indiana, 46202, United States

RECRUITING

Johns Hopkins Medical Institute

Baltimore, Maryland, 21287, United States

RECRUITING

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Corewell Health

Grand Rapids, Michigan, 49503, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

UNC Chapel Hill

Chapel Hill, North Carolina, 27599, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Cleveland Clinic Children's

Cleveland, Ohio, 44195, United States

RECRUITING

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98101, United States

RECRUITING

University of Wisconsin, Madison

Madison, Wisconsin, 53715, United States

RECRUITING

Sydney Children's Hospital, Randwick

Randwick, New South Wales, 2031, Australia

RECRUITING

Children's Health Queensland Hospital and Health

South Brisbane, Queensland, 4101, Australia

RECRUITING

Monash Health

Clayton, Victoria, 3168, Australia

RECRUITING

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

RECRUITING

Murdoch Children's Research Institute

Parkville, Victoria, 3052, Australia

RECRUITING

UC Louvain

Ottignies-Louvain-la-Neuve, Belgium

RECRUITING

University of Halle

Halle, Germany, Germany

RECRUITING

Ospedale Pediatrico Bambino Gesù IRCCS

Roma, Italy

RECRUITING

A.O.U Città della Salute e della Scienza di Torino

Torino, Italy

RECRUITING

Hospital Sant Joan de Deu

Barcelona, Spain

RECRUITING

Hospital Universitario La Paz

Madrid, Spain

RECRUITING

Great Ormond Street Hospital for Children

London, United Kingdom

RECRUITING

MeSH Terms

Conditions

Lymphatic Abnormalities; Vascular Malformations; Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi; Klippel-Trenaunay-Weber Syndrome; Megalencephaly cutis marmorata telangiectatica congenita

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cardiovascular Abnormalities; Cardiovascular Diseases; Angiomatosis; Vascular Diseases

Central Study Contacts

Relay Therapeutics, Inc

CONTACT

617-322-0731; ClinicalTrials@relaytx.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 17, 2025
• First Posted: January 23, 2025
• Study Start: June 13, 2025
• Primary Completion (Estimated): July 1, 2031
• Study Completion (Estimated): October 1, 2031
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); AU (5); US (19); IT (2); ES (2); GB (1); DE (1)