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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 277
- 试验地点
- 41
- 主要终点
- Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≥
- •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.
排除标准
- •Known hypersensitivity to RLY-
- •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.
研究组 & 干预措施
Part 1, Group 2
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.
干预措施: RLY-2608 (Drug)
Part 1, Group 1
RLY-2608 for patients ≥12 years old with PROS or malformations with PIK3CA mutation. Multiple doses of RLY-2608 for oral administration.
干预措施: RLY-2608 (Drug)
Part 3, Arm 1
Adult (>18 yo) 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.
干预措施: RLY-2608 (Drug)
Part 3, Arm 2
Adult (>18 yo) and pediatric (6 to <18 yo) participants with PROS and malformations with PIK3CA mutation will be randomized to receive placebo.
干预措施: Placebo (Drug)
Part 2, Group 1
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.
干预措施: RLY-2608 (Drug)
Part 2, Group 3
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.
干预措施: RLY-2608 (Drug)
Part 2, Group 2
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.
干预措施: RLY-2608 (Drug)
Part 1, Group 3
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.
干预措施: RLY-2608 (Drug)
结局指标
主要结局
Parts 1 and 2: Determination of a recommended phase 2 dose RP2D(s) for Groups 1, 2, and 3
时间窗: 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).
时间窗: Cycle 1 of treatment and at the end of every cycle until study discontinuation
Part 3: Percentage of participants with volumetric Response.
时间窗: Baseline, Week 24
次要结局
- Part 1 and 2: Percent change from baseline in lesion volume(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(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: 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)
- 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 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)