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)

Официальное название

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)

Обзор

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)

Вмешательства

• Препарат CYH33
  CYH33: Participants will receive oral CYH33 once daily. The starting dose for adults in Phase I is 10 mg QD; adolescents begin at 5 mg QD. In Phase II, patients will receive RP2D determined in the Phase I study.
• Препарат Placebo
  Placebo: Matching placebo tablets will be administered once daily during the double-blind period of the Phase II PRVM cohort. Patients randomized to placebo will switch to CYH33 at the end of the blinded phase.

Первичные конечные точки

• Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D) [Срок оценки: 27 weeks]
• Phase II PROS Cohort: BIRC-assessed objective response rate (ORR) at Week 24 [Срок оценки: Baseline to 24weeks]
• Phase II PRVM Cohort: BIRC-assessed objective response rate (ORR) at Week 24 [Срок оценки: Baseline to 24weeks]

Вторичные конечные точки (12)

• Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Area Under the Curve from 0 to 24 hours (AUC0-24h) [Срок оценки: 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) [Срок оценки: 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: Minimum Concentration (Cmin) [Срок оценки: Pre-dose on Day 29.]
• Phase I: Pharmacokinetics of CYH33 and its metabolites in the study population: Time to Maximum Concentration (Tmax) [Срок оценки: 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) [Срок оценки: Pre-dose and at 1, 2, 4, 6, 8, and 24 hours post-dose on Day 1 and Day 29.]
• Phase I: The response rate and target lesion volume reduction rate as assessed by the investigators at each dose level [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Up to approximately 48 months]
• Phase I: Frequency and severity of adverse events [Срок оценки: Up to approximately 48 months]
• Phase II : BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort) [Срок оценки: Week 48]
• Phase II: BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort) [Срок оценки: Week27]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 8 центров

• Capital Center for Children's Health, Capital Medical University — Пекин
• Plastic Surgery Hospital, Chinese Academy of Medical Sciences — Пекин
• Fujian Medical University Union Hospital — Фучжоу
• Guangzhou Women and Children's Medical Center — Гуанчжоу
• Henan Provincial People's Hospital — Чжэнчжоу
• The Second Xiangya Hospital of Central South University — Чанша
• Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine — Шанхай
• West China Hospital of Sichuan University — Чэнду

Япония · 7 центров

• Tonan Hospital — Sapporo
• National Hospital Organization Kobe Medical Center — Kobe
• Yokohama City University Hospital — Yokohama
• Tohoku University Hospital — Sendai
• Shinshu University Hospital — Matsumoto
• Kyorin University Hospital — Mitaka
• Gifu University Hospital — Gifu

Идентификаторы

NCT: NCT06975618 · CYH33-G208

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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