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

Relay Therapeutics

Status and phase: Enrolling; Phase 2

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

Treatments: Drug: Placebo; Drug: RLY-2608

Study type: Interventional

Funder types: Industry

Identifiers

NCT06789913

2024-518895-30-00 (EU Trial (CTIS) Number)

RLY-2608-201

Details and patient eligibility

About

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.

Enrollment: 280 estimated patients

Sex: All

Ages: 2+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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280 participants in 8 patient groups, including a placebo group

Part 1, Group 1

Experimental group

Description:

RLY-2608 for patients ≥12 years old with PROS or malformations with PIK3CA mutation. Multiple doses of RLY-2608 for oral administration.

Treatment:

Drug: RLY-2608

Part 1, Group 2

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 1, Group 3

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 2, Group 1

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 2, Group 2

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 2, Group 3

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 3, Arm 1

Experimental group

Description:

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.

Treatment:

Drug: RLY-2608

Part 3, Arm 2

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo