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)
- Conditions
- PIK3CA-Related Overgrowth Spectrum (PROS)PIK3CA-related Vascular Malformations (PRVM)
- Interventions
- 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 130
- The patient or the patient's guardian (if applicable) voluntarily signs the Informed Consent Form.
- At the time of signing the Informed Consent, the age of adult patients should be ≥ 18 years, and the age of adolescent patients should be ≥ 12 years and < 18 years of age.
- Patient diagnosed with PIK3CA-related overgrowth spectrum (PROS) or PIK3CA-related vascular malformation (PRVM).
- Patients should be tested to have adequate organ and bone marrow function, within 28 days of the screening period.
- Patients who have received any prior treatment with PI3K or AKT inhibitors.
- Received a blood transfusion or platelet transfusion within 2 weeks prior to the administration of the investigational drug.
- Patients with clinically significant cardiovascular disease.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort1：Adult cohort:； Cohort2：Adolescent cohort； CYH33 Cohort1：Adult cohort: Participants will receive oral CYH33 once daily. An initial dose of 10 mg QD and possible additional dose levels (e.g. 15mg, 20mg QD) will be evaluated in the dose escalation stage and dose expansion stage in Phase I. For Phase II, the starting dose of CYH33 will be selected based on the RP2D determined in the Phase I study. Cohort2：Adolescent cohort: Participants will receive oral CYH33 once daily. An initial dose of 5 mg QD and possible additional dose levels (e.g. 10mg, 15mg QD) will be evaluated in the dose escalation stage and dose expansion stage in Phase I. For Phase II, the starting dose of CYH33 will be selected based on the RP2D determined in the Phase I study.
- 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: The response rate as assessed by BIRC in each cohort 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.
- Secondary Outcome Measures
Name Time Method 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 h post-dose on Cycle2Day1 CLss/F of CYH33 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 h post-dose on Cycle1Day1 and Cycle2Day1 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 h post-dose on Cycle1Day1 and Cycle2Day1 Cmax 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: Minimum Concentration (Cmin) Pre-dose on Cycle2Day1 Cmin of CYH33 and its metabolite I27 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 h post-dose on Cycle1Day1 and Cycle2Day1 Tmax of CYH33 and its metabolite I27 following drug administration will be assessed.
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: 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: 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: The reduction rate of target lesion volume as assessed by BIRC in each cohort Week27 The proportion of patients with reduced target lesion volume (assessed by BIRC) compared to baseline will be reported.
Phase II: The response rate and reduction rate of target lesion volume as assessed by the investigators in each cohort Week27 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 II: 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 II: 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 II: - 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 II: 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: Plasma concentrations of CYH33 and its metabolite I27 in the study population 4 h post-dose on Day 1 of Cycles 1, 2, 3, 4, and 5, and on the day of the EOT visit Plasma concentrations of CYH33 and its metabolite I27 will be measured.
Trial Locations
- Locations (4)
Capital Institute of Pediatrics
🇨🇳Beijing, Beijing, China
Plastic Surgery Hospital, Chinese Academy of Medical Sciences
🇨🇳Beijing, Beijing, China
Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine
🇨🇳Shanghai, Shanghai, China
West China Hospital of Sichuan University
🇨🇳Chengdu, Sichuan, China