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)

Official title

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)

Overview

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)

Interventions

• Drug 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.
• Drug 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.

Primary outcome measures

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

Secondary outcome measures (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) [Time frame: 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) [Time frame: 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) [Time frame: Pre-dose on Day 29.]
• Phase I: Pharmacokinetics of CYH33 and its metabolites in the study population: Time to Maximum Concentration (Tmax) [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Up to approximately 48 months]
• Phase I: Frequency and severity of adverse events [Time frame: Up to approximately 48 months]
• Phase II : BIRC-assessed ORR at Week 48 (PROS cohort and PRVM cohort) [Time frame: Week 48]
• Phase II: BIRC-assessed ORR at Week 8 (Double-blind Period in PRVM cohort) [Time frame: Week27]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 8 centers

• Capital Center for Children's Health, Capital Medical University — Beijing
• Plastic Surgery Hospital, Chinese Academy of Medical Sciences — Beijing
• Fujian Medical University Union Hospital — Fuzhou
• Guangzhou Women and Children's Medical Center — Guangzhou
• Henan Provincial People's Hospital — Zhengzhou
• The Second Xiangya Hospital of Central South University — Changsha
• Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine — Shanghai
• West China Hospital of Sichuan University — Chengdu

Japan · 7 centers

• 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

Identifiers

NCT: NCT06975618 · CYH33-G208

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗