A Phase I/II, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Efficacy of CYH33 (a Selective PI3Kα Inhibitor) in Patients With PIK3CA-related Overgrowth Spectrum (PROS) and PIK3CA-related Vascular Malformations (PRVM)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 141
- 试验地点
- 19
- 主要终点
- Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D)
研究概览
简要总结
This study is a multi-center, open-label, single arm, phase I/II study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of CYH33 in patients with PIK3CA-related overgrowth spectrum (PROS) and PIK3CA-related vascular malformations (PRVM)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
The Phase I and Phase II PROS cohorts are both open-label, whereas the Phase II PRVM cohort is double-blind, with participants, care providers, investigators and outcome assessors unaware of the treatment assignments.
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient or the patient's legal guardian (if applicable) voluntarily signs the Informed Consent Form.
- •At the time of signing the informed consent, adult patients should be ≥18 years old (or meet the legal adult age according to local regulations), and adolescent patients should be ≥12 years old and <18 years old (or meet the legal definition of adolescent according to local regulations; additionally, adolescent patients should weigh ≥35 kg).
- •The patient is diagnosed with PIK3CA-related overgrowth spectrum (PROS) or PIK3CA-related vascular malformations (PRVM), and provides a report confirming PIK3CA mutation detected by local laboratory or the Sponsor-designated central laboratory, with at least one measurable lesion related to PROS or PRVM.
- •Patients should demonstrate adequate organ and bone marrow function during the 28-day screening period.
排除标准
- •PROS patients presenting solely with isolated macrodactyly, epidermal nevi/nevus, and megalencephaly (only one clinical feature or any combination of these three features) without other PROS-related lesions.
- •Patients who have received any systemic treatment for PROS or PRVM within 8 weeks prior to the first dose of study drug, or any drug treatment for PROS or PRVM (e.g., mTOR inhibitors) within 28 days prior to the first dose of study drug.
- •Patients who have previously received any PI3K inhibitor treatment.
研究组 & 干预措施
Arm 1：Adult cohort:；
Phase I Adult Cohort: Adult patients with PIK3CA-related overgrowth spectrum (PROS) or PIK3CA-related vascular malformations (PRVM) will receive escalating oral doses of CYH33 to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D). Expansion cohorts may be opened to further assess safety, tolerability, pharmacokinetics, and preliminary efficacy.
干预措施: CYH33 (Drug)
Arm 4 : Phase II PRVM Cohort
Phase II PRVM Cohort: Adult and adolescent patients with PRVM will be randomized 2:1 to CYH33 or placebo during double-blind period. After 8 weeks of treatment, all patients will enter an open-label extension phase to receive CYH33. Treatment continues until disease progression, unacceptable toxicity, or withdrawal.
干预措施: CYH33 (Drug)
Arm 4 : Phase II PRVM Cohort
Phase II PRVM Cohort: Adult and adolescent patients with PRVM will be randomized 2:1 to CYH33 or placebo during double-blind period. After 8 weeks of treatment, all patients will enter an open-label extension phase to receive CYH33. Treatment continues until disease progression, unacceptable toxicity, or withdrawal.
干预措施: Placebo (Drug)
Arm 2: Phase I Adolescent Cohort
Phase I Adolescent Cohort: Adolescent patients with PIK3CA-related overgrowth spectrum (PROS) or PIK3CA-related vascular malformations (PRVM) will receive escalating oral doses of CYH33 to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D). Expansion cohorts may be opened to further assess safety, tolerability, pharmacokinetics, and preliminary efficacy.
干预措施: CYH33 (Drug)
Arm 3 : Phase II PROS Cohort
Phase II PROS Cohort: An open-label, single-arm cohort. Adult and adolescent patients with PROS will receive CYH33 at RP2D. Dose escalation may be allowed based on tolerability and clinical assessment. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal.
干预措施: CYH33 (Drug)
结局指标
主要结局
Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D)
时间窗: 27 weeks
To evaluate the safety and tolerability of CYH33 and determine the maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D) of CYH33 in adult and adolescent patients
Phase II PRVM Cohort: BIRC-assessed objective response rate (ORR) at Week 24
时间窗: Baseline to 24weeks
Proportion of patients achieving ≥20% reduction from baseline in the sum of target lesion volumes, with no progression of non-target lesions and no new lesions, as assessed by blinded independent review committee (BIRC).
Phase II PROS Cohort: BIRC-assessed objective response rate (ORR) at Week 24
时间窗: Baseline to 24weeks
Proportion of patients achieving ≥20% reduction from baseline in the sum of target lesion volumes, with no progression of non-target lesions and no new lesions, as assessed by blinded independent review committee (BIRC).
Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D)
时间窗: 27 weeks
To evaluate the safety and tolerability of CYH33 and determine the maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D) of CYH33 in adult and adolescent patients
次要结局
- Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Minimum Concentration (Cmin)(Pre-dose on Day 29.)
- Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Area Under the Curve from 0 to 24 hours (AUC0-24h)(Pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose on Day 1 and Day 29.)
- Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Maximum Concentration (Cmax)(Pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose on Day 1 and Day 29.)
- Phase I: Pharmacokinetics of CYH33 in the study population: Steady-State Apparent Clearance (CLss/F)(Pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose on Day 1 and Day 29.)
- Phase I: Pharmacokinetics of CYH33 and its metabolites in the study population: Time to Maximum Concentration (Tmax)(Pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose on Day 1 and Day 29.)
- Phase I: The changes from baseline in the quality of life scores at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)
- Phase I: The response rate and target lesion volume reduction rate as assessed by the investigators at each dose level(week 27)
- Phase I: The changes from baseline in the Brief Pain Inventory (BPI) Worst Pain Intensity Numerical Rating score at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)
- Phase I: The changes from baseline in the Patient Global Impression of Change scale at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)
- Phase I: Frequency and severity of adverse events(Up to approximately 48 months)
- Phase II : BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort)(Week 48)
- Phase II: BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort)(Week27)
- Phase II: BIRC-assessed ORR at Weeks 8 and 16 (PROS cohort and PRVM cohort)(Weeks 8 and Week 16)
- Phase II : Change from Baseline in Target Lesion Volume (PROS cohort and PRVM cohort)(Up to approximately 48 months)
- Phase II: Investigator-assessed overall clinical response (PROS cohort and PRVM cohort)(Up to approximately 48 months)
- Phase II: Change from Baseline in Patient-Reported Outcomes (PROS cohort and PRVM cohort)(Up to approximately 48 months)
- Phase II: Safety and Tolerability of CYH33 (PROS cohort and PRVM cohort)(Up to approximately 48 months)
- Phase II :Plasma Drug Concentrations of CYH33 and Metabolite I27(Up to 5 cycles (approximately 20 weeks))
- Phase I: Frequency and severity of adverse events(Up to approximately 48 months)
- Phase I: The response rate and target lesion volume reduction rate as assessed by the investigators at each dose level(week 27)
- Phase I: The changes from baseline in the Brief Pain Inventory (BPI) Worst Pain Intensity Numerical Rating score at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)
- Phase I: The changes from baseline in the Patient Global Impression of Change scale at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)
- Phase I: The changes from baseline in the quality of life scores at each dose level, based on the patient-reported outcome (PRO) diary(Up to approximately 48 months)