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)

Phase 2RecruitingNCT06975618

Haihe Biopharma Co., Ltd.141 enrolled

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)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

141

Conditions

Interventions

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.

PlaceboDRUG

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.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Key inclusion criteria: 1. The patient or the patient's legal guardian (if applicable) voluntarily signs the Informed Consent Form. 2. 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). 3. 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. 4. Patients should demonstrate adequate organ and bone marrow function during the 28-day screening period. Key exclusion criteria: 1. 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. 2. 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. 3. Patients who have previously received any PI3K inhibitor treatment.

Locations (4)

Capital Institute of Pediatrics

Beijing, Beijing Municipality, China

RECRUITING

Plastic Surgery Hospital, Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, China

RECRUITING

Shanghai Ninth People Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, Shanghai Municipality, China

RECRUITING

West China Hospital of Sichuan University

Chengdu, Sichuan, China

RECRUITING

Outcomes

Primary Outcomes

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

Time frame: 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).

Time frame: Baseline to 24weeks

Phase II PRVM Cohort: BIRC-assessed objective response rate (ORR) at Week 24

Time frame: Baseline to 24weeks

Secondary Outcomes

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.

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)

Cmax of CYH33 and its metabolite I27 following drug administration will be assessed.

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)

Cmin of CYH33 and its metabolite I27 following drug administration will be assessed.

Time frame: 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.

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)

CLss/F of CYH33 following drug administration will be assessed.

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

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.

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

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.

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

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.

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

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.

Time frame: 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).

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Up to approximately 48 months

Phase II :Plasma Drug Concentrations of CYH33 and Metabolite I27

Plasma Drug Concentrations of CYH33 and Metabolite I27

Time frame: Up to 5 cycles (approximately 20 weeks)

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)

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts