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)

Official 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

Overview

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.

Interventions

• Drug RLY-2608
  RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
• Drug Placebo
  RLY-2608 matched-placebo

Primary outcome measures

• 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]
• 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]
• Part 3: Percentage of participants with volumetric Response. [Time frame: Baseline, Week 24]

Secondary outcome measures (9)

• Part 1 and 2: Percent change from baseline in lesion volume [Time frame: 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]
• Part 1 and 2: Percentage of participants with volumetric response [Time frame: Baseline, week 12, week 24]
• 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]
• Part 1 and 2: PIK3CA mutational status in lesional fluid and/or tissue [Time frame: 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]
• Part 3: Change from baseline by age-appropriate PROMIS Profile [Time frame: Approximately once a month until end of treatment]
• 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]
• 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]

Eligibility criteria

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.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 20 centers

• Phoenix Children's Hospital — Phoenix
• Arkansas Children's Hospital — Little Rock
• University of California, Los Angeles — Los Angeles
• Stanford University — Palo Alto
• University of California, San Francisco — San Francisco
• Children's Hospital Colorado — Aurora
• Children's Hospital of Atlanta — Atlanta
• Riley Children's Hospital — Indianapolis
• … and 12 more centers

Australia · 5 centers

• Sydney Children's Hospital, Randwick — Randwick
• Children's Health Queensland Hospital and Health — South Brisbane
• Monash Health — Clayton
• Royal Melbourne Hospital — Parkville
• Murdoch Children's Research Institute — Parkville

Spain · 3 centers

• Hospital Universitario A Coruña — A Coruña
• Hospital Sant Joan de Deu — Barcelona
• Hospital Universitario La Paz — Madrid

Italy · 2 centers

• Ospedale Pediatrico Bambino Gesù IRCCS — Roma
• A.O.U Città della Salute e della Scienza di Torino — Torino

United Kingdom · 2 centers

• Chelsea and Westminster Hospital — London
• Great Ormond Street Hospital for Children — London

Belgium · 1 center

• UC Louvain — Ottignies-Louvain-la-Neuve

Germany · 1 center

• University of Halle — Halle

Identifiers

NCT: NCT06789913 · RLY-2608-201 · 2024-518895-30-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗