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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)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1：Adult cohort:； | Experimental | 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. |
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| Arm 2: Phase I Adolescent Cohort | Experimental | 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. |
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| Arm 3 : Phase II PROS Cohort | Experimental | 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. |
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| Arm 4 : Phase II PRVM Cohort | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CYH33 | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Phase I: The maximum tolerated dose (MTD) and/or phase II recommended dose (RP2D) | 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 | 27 weeks |
| Phase II PROS Cohort: BIRC-assessed objective response rate (ORR) at Week 24 | 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). | Baseline to 24weeks |
| Phase II PRVM Cohort: BIRC-assessed objective response rate (ORR) at Week 24 | 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). | Baseline to 24weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Area Under the Curve from 0 to 24 hours (AUC0-24h) | AUC0-24h of CYH33 and its metabolite I27 following drug administration will be assessed. | 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) |
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Key inclusion criteria:
Key exclusion criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xiaoxi Lin, MD | Contact | +86-13701997136 | linxiaoxi@126.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Capital Center for Children's Health, Capital Medical University | Recruiting | Beijing | Beijing Municipality | 100000 | China |
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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.
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| Placebo | Drug | 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. |
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Cmax of CYH33 and its metabolite I27 following drug administration will be assessed. |
| 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) | Cmin of CYH33 and its metabolite I27 following drug administration will be assessed. | Pre-dose on Day 29. |
| Phase I: Pharmacokinetics of CYH33 and its metabolites in the study population: Time to Maximum Concentration (Tmax) | Tmax of CYH33 and its metabolite I27 following drug administration will be assessed. | 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) | CLss/F of CYH33 following drug administration will be assessed. | 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 | 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. | 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 | 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. | 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 | 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. | 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 | 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. | Up to approximately 48 months |
| Phase I: Frequency and severity of adverse events | The type, incidence, and severity of adverse events (AEs) (assessed according to the CTCAE Version 5.0 criteria). | Up to approximately 48 months |
| Phase II : BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort) | BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48 | Week 48 |
| Phase II: BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort) | BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort) Time Frame: From randomization to Week 8 | Week27 |
| Phase II: BIRC-assessed ORR at Weeks 8 and 16 (PROS cohort and PRVM cohort) | 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 | Weeks 8 and Week 16 |
| Phase II : Change from Baseline in Target Lesion Volume (PROS cohort and PRVM cohort) | Change from Baseline in Target Lesion Volume (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48 | Up to approximately 48 months |
| Phase II: Investigator-assessed overall clinical response (PROS cohort and PRVM cohort) | Investigator-assessed overall clinical response (PROS cohort and PRVM cohort) Time Frame: From start of CYH33 treatment to Week 48 | Up to approximately 48 months |
| Phase II: Change from Baseline in Patient-Reported Outcomes (PROS cohort and PRVM cohort) | Change from Baseline in Patient-Reported Outcomes (PROS cohort and PRVM cohort) Time Frame: Up to approximately 48 months | Up to approximately 48 months |
| Phase II: Safety and Tolerability of CYH33 (PROS cohort and PRVM cohort) | Safety and Tolerability of CYH33 (PROS cohort and PRVM cohort) Time Frame: Up to approximately 48 months | Up to approximately 48 months |
| Phase II :Plasma Drug Concentrations of CYH33 and Metabolite I27 | Plasma Drug Concentrations of CYH33 and Metabolite I27 | Up to 5 cycles (approximately 20 weeks) |
| Plastic Surgery Hospital, Chinese Academy of Medical Sciences | Recruiting | Beijing | Beijing Municipality | 100144 | China |
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| Fujian Medical University Union Hospital | Recruiting | Fuzhou | Fujian | 350001 | China |
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| Guangzhou Women and Children's Medical Center | Not yet recruiting | Guangzhou | Guangdong | 510000 | China |
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| Henan Provincial People's Hospital | Recruiting | Zhengzhou | Henan | 450003 | China |
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| The Second Xiangya Hospital of Central South University | Recruiting | Changsha | Hunan | 410011 | China |
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| Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine | Recruiting | Shanghai | Shanghai Municipality | 200011 | China |
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| West China Hospital of Sichuan University | Recruiting | Chengdu | Sichuan | 610041 | China |
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| Tonan Hospital | Recruiting | Sapporo | Hokkaido | 060-0004 | Japan |
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| National Hospital Organization Kobe Medical Center | Recruiting | Kobe | Hyōgo | 654-0155 | Japan |
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| Yokohama City University Hospital | Recruiting | Yokohama | Kanagawa | 236-0004 | Japan |
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| Tohoku University Hospital | Recruiting | Sendai | Miyagi | 980-8574 | Japan |
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| Shinshu University Hospital | Recruiting | Matsumoto | Nagano | 390-8621 | Japan |
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| Kyorin University Hospital | Recruiting | Mitaka | Tokyo | 181-8611 | Japan |
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| Gifu University Hospital | Recruiting | Gifu | 501-1194 | Japan |
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| ID | Term |
|---|---|
| C000634149 | CYH33 |
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