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)

Not Applicable

Recruiting

• Conditions: PIK3CA-Related Overgrowth Spectrum (PROS); PIK3CA-related Vascular Malformations (PRVM)
• Interventions: Drug: CYH33; Drug: Placebo

• Registration Number: NCT06975618

Brief Summary

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)

Detailed Description

Not available

Study Timeline

• Study Start: 2023-08-22
• Study First Submitted: 2025-04-28
• Study First Submitted QC: 2025-05-13
• Study First Posted: 2025-05-16
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-23
• Last Update Posted: 2025-09-24
• Primary Completion: 2029-12-31
• Study Completion: 2029-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 141

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1：Adult cohort:；	CYH33	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.
Arm 2: Phase I Adolescent Cohort	CYH33	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.
Arm 3 : Phase II PROS Cohort	CYH33	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.
Arm 4 : Phase II PRVM Cohort	CYH33	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.
Arm 4 : Phase II PRVM Cohort	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D)	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	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	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).

Secondary Outcome Measures

Name	Time	Method
Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Minimum Concentration (Cmin)	Pre-dose on Day 29.	Cmin of CYH33 and its metabolite I27 following drug administration will be assessed.
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.	AUC0-24h of CYH33 and its metabolite I27 following drug administration will be assessed.
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.	Cmax of CYH33 and its metabolite I27 following drug administration will be assessed.
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.	CLss/F of CYH33 following drug administration will be assessed.
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.	Tmax of CYH33 and its metabolite I27 following drug administration will be assessed.
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	The Quality of Life Scale (EQ-5D-5L) consists of two parts. Part 1 assesses five quality-of-life-related indicators, with each indicator graded into five distinct levels for self-evaluation by the patient. Part 2 consists of patients' self-assessment of health status, with a maximum score of 100 points and a minimum score of 0 points.
Phase I: The response rate and target lesion volume reduction rate as assessed by the investigators at each dose level	week 27	A responder is defined as a ≥ 20% reduction in target lesion volume from baseline and in absence of progression of non-target lesions and without new lesions. The proportion of patients with reduced target lesion volume compared to baseline will also be assessed.
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	Pain is categorized into 11 levels from 0 to 10, where 0 indicates no pain at all and 10 indicates the most severe pain imaginable. Patients should assess and record their pain levels over the past 24 hours in the patient diary at each scheduled assessment visit.
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	Patients will compare their global impression of symptom changes with the pretreatment status, then categorize them into the following 7 grades: significantly relieved, moderately relieved, minimally relieved, no change, minimally worse, moderately worse, or significantly worse at each scheduled assessment visit.
Phase I: Frequency and severity of adverse events	Up to approximately 48 months	The type, incidence, and severity of adverse events (AEs) (assessed according to the CTCAE Version 5.0 criteria).
Phase II : BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort)	Week 48	BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48
Phase II: BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort)	Week27	BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort) Time Frame: From randomization to Week 8
Phase II: BIRC-assessed ORR at Weeks 8 and 16 (PROS cohort and PRVM cohort)	Weeks 8 and Week 16	BIRC-assessed ORR at Weeks 8 and 16 (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Weeks 8 and 16
Phase II : Change from Baseline in Target Lesion Volume (PROS cohort and PRVM cohort)	Up to approximately 48 months	Change from Baseline in Target Lesion Volume (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48
Phase II: Investigator-assessed overall clinical response (PROS cohort and PRVM cohort)	Up to approximately 48 months	Investigator-assessed overall clinical response (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48
Phase II: Change from Baseline in Patient-Reported Outcomes (PROS cohort and PRVM cohort)	Up to approximately 48 months	Change from Baseline in Patient-Reported Outcomes (PROS cohort and PRVM cohort) Time Frame: Up to approximately 48 months
Phase II: Safety and Tolerability of CYH33 (PROS cohort and PRVM cohort)	Up to approximately 48 months	Safety and Tolerability of CYH33 (PROS cohort and PRVM cohort) Time Frame: Up to approximately 48 months
Phase II :Plasma Drug Concentrations of CYH33 and Metabolite I27	Up to 5 cycles (approximately 20 weeks)	Plasma Drug Concentrations of CYH33 and Metabolite I27

Trial Locations

Locations (4)

Capital Institute of Pediatrics; 🇨🇳 Beijing, Beijing Municipality, China

Plastic Surgery Hospital, Chinese Academy of Medical Sciences; 🇨🇳 Beijing, Beijing Municipality, China

Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine; 🇨🇳 Shanghai, Shanghai Municipality, China

West China Hospital of Sichuan University; 🇨🇳 Chengdu, Sichuan, China