PIK3CA-Related Overgrowth Spectrum (PROS), Lymphatic Malformations, Vascular Malformations, PIK3CA Mutation, CLOVES Syndrome, Klippel Trenaunay Syndrome, Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)
Conditions
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.
Interventions
DRUGRLY-2608
RLY-2608 is a mutant-selective, oral PI3Kα inhibitor.
DRUGPlacebo
RLY-2608 matched-placebo
Sponsors
Relay Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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: Percent change from baseline in lesion volume | Baseline, Week 24 |
| Part 3: Change from baseline by age-appropriate PROMIS Profile | Approximately once a month until end of treatment |
| Part 3: Change from baseline in EQ-5D, EQ-5D-Y, or EQ-5D-Y Proxy | Approximately once a month until end of treatment |
| Part 3: Percent change from baseline in lesion volume | Approximately every 3 months for approximately the first year, and then every 6 months during treatment |
| Part 3: Percentage of participants with improvement compared to baseline based on PGI-S, PGI-C and IGIC | Approximately once a month until end of treatment |
| 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 |
Countries
Australia, Belgium, Italy, Spain, United Kingdom, United States
Contacts
Primary ContactRelay Therapeutics, Inc
Outcome results
None listed