Clinical trial 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: PIK3CA-Related Overgrowth Spectrum (PROS)
Lymphatic Malformations
Vascular Malformations
PIK3CA Mutation
CLOVES Syndrome
Klippel Trenaunay Syndrome
Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)
Lead sponsor: Relay Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2025-01-23
Enrollment: 280
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: Key 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.

Primary outcomes:
measure: Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3
timeFrame: Cycle 1 (4-week cycle) of treatment and at the end of every cycle (4-week cycles) until study discontinuation
measure: 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).
timeFrame: Cycle 1 (4-week cycle) of treatment and at the end of every cycle (4-week cycles) until study discontinuation
measure: Part 3: Percentage of participants with volumetric Response.
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Part 1 and 2: Percent change from baseline in lesion volume
timeFrame: Baseline, Week 24
measure: 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
timeFrame: Approximately every 3 months for approximately the first year, and then every 6 months during treatment
measure: Part 1 and 2: Percentage of participants with volumetric response
timeFrame: Baseline, week 12, week 24
measure: Part 1 and 2: Plasma concentrations and PK parameters of RLY-2608
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle), then again at Cycle 4 and Cycle 7
measure: Part 1 and 2: PIK3CA mutational status in lesional fluid and/or tissue
timeFrame: Prior to enrollment
measure: Part 3: Percentage of participants with improvement compared to baseline based on PGI-S, PGI-C and IGIC
timeFrame: Approximately once a month until end of treatment
measure: Part 3: Change from baseline by age-appropriate PROMIS Profile
timeFrame: Approximately once a month until end of treatment
measure: Part 3: Change from baseline in EQ-5D-5L, EQ-5D-Y-3L, or EQ-5D-Y-3L Proxy 1
timeFrame: Approximately once a month until end of treatment
measure: Part 3: Percent change from baseline in lesion volume
timeFrame: Approximately every 3 months for approximately the first year, and then every 6 months during treatment
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
Study officials:
References: