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NCT Number: NCT06789913

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 (The ReInspire Study)

This is a 3-part Phase 2 randomized study evaluating the safety and efficacy of the mutant-selective PI3Kα inhibitor, zovegalisib (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.

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Key information

Conditions

PIK3CA-related Overgrowth Spectrum (PROS) Angiomatosis CLOVES Syndrome Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi Congenital, Hereditary, and Neonatal Diseases and Abnormalities Hemic and Lymphatic Diseases Klippel Trenaunay Syndrome Klippel-Trenaunay-Weber Syndrome Lymphatic Abnormalities Lymphatic Diseases Lymphatic Malformations Megalencephaly cutis marmorata telangiectatica congenita Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP) PIK3CA Mutation Vascular Anomalies Vascular Diseases Vascular Malformations

Age range

2 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Sydney Children's Hospital, Randwick, Randwick, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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, with the sponsor's approval, 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:

  • Known hypersensitivity to RLY-2608.
  • 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.

Treatment and study plan

RLY-2608

Drug

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

Placebo

Drug

RLY-2608 matched-placebo

Primary outcomes

  1. 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

  2. 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

  3. Part 3: Percentage of participants with volumetric Response.

    Time frame: Baseline, Week 24

Secondary outcomes

  1. Part 1 and 2: Percent change from baseline in lesion volume

    Time frame: Baseline, Week 24

  2. 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

  3. Part 1 and 2: Percentage of participants with volumetric response

    Time frame: Baseline, week 12, week 24

  4. 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

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

    Time frame: Prior to enrollment

  6. 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

  7. Part 3: Change from baseline by age-appropriate PROMIS Profile

    Time frame: Approximately once a month until end of treatment

  8. 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

  9. 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

Study contacts

Contact information is provided by the study sponsor or research team.

Relay Therapeutics, Inc

CONTACT

[email protected]

617-322-0731

Sponsors and collaborators

Lead sponsor

Relay Therapeutics, Inc.

Industry

Registry information

Official study title

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

Important dates

Study start
2025
Primary completion
2031
Study completion
2031
First posted
Jan 23, 2025
Registry last updated
Jun 12, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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