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)

NCT06975618 | Recruiting Phase 1 DMC

• 1 other identifier: CYH33-G208
• Study Type: interventional
• Target: 141
• Locations: 1 country
• Sites: 4

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)

Conditions

PIK3CA-Related Overgrowth Spectrum (PROS); PIK3CA-related Vascular Malformations (PRVM)

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (18)

• 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.

• 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.

• Phase I: Pharmacokinetics of CYH33 and its metabolite I27 in the study population: Minimum Concentration (Cmin)

  Pre-dose on Day 29.

• 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.

• 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.

Study Arms (4)

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.

Drug: CYH33

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.

Drug: CYH33

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.

Drug: CYH33

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.

Drug: CYH33; Drug: Placebo

Interventions

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.

Arm 1：Adult cohort:；; Arm 2: Phase I Adolescent Cohort; Arm 3 : Phase II PROS Cohort; Arm 4 : Phase II PRVM Cohort

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.

Arm 4 : Phase II PRVM Cohort

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Haihe Biopharma Co., Ltd.: lead

Study Sites (4)

Capital Institute of Pediatrics

Beijing, Beijing Municipality, 100000, China

RECRUITING

Plastic Surgery Hospital, Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, 100144, China

RECRUITING

Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, Shanghai Municipality, 200011, China

RECRUITING

West China Hospital of Sichuan University

Chengdu, Sichuan, 610041, China

RECRUITING

MeSH Terms

Interventions

CYH33

Central Study Contacts

Xiaoxi Lin, MD

CONTACT

+86-13701997136; linxiaoxi@126.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2025
• First Posted: May 16, 2025
• Study Start: August 22, 2023
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: September 24, 2025

Record last verified: 2025-09

Locations

CN (4)