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A Phase I/II, multicenter study to evaluate the safety, tolerability, pharmacokinetics characteristics, and efficacy of CYH33 in patinets with PIK3CA related overgrowth spectrum (PROS) and PIK3CA related vascular malformations (PRVM) (A Phase I/II study of CYH33 in Patients with PROS and PRVM)

A Phase I/II, multicenter study to evaluate the safety, tolerability, pharmacokinetics characteristics, and efficacy of CYH33 in patinets with PIK3CA related overgrowth spectrum (PROS) and PIK3CA related vascular malformations (PRVM) (A Phase I/II study of CYH33 in Patients with PROS and PRVM)

Sunagawa Yoshihiro

Haihe Biopharma K. K.

1403, 5-2-33, Akasaka, Minato-ku,Tokyo

sunagawa.yoshihiro@haihepharma.com

Sunagawa Yoshihiro

Haihe Biopharma K. K.

1403, 5-2-33, Akasaka, Minato-ku,Tokyo

+81-3-6441-0878

sunagawa.yoshihiro@haihepharma.com

Recruiting

Jan. 01, 2026

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

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 vascular malformation and/or overgrowth syndrome (PRVOs), including 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 (For the Phase II Study PROS Cohort, patients with PIK3CA mutation confirmed by local laboratory test may proceed to clinical screening and can be enrolled if eligible, but must simultaneously provide fresh or archived tissue samples for retrospective confirmation of PIK3CA mutation by central laboratory test, whereas for the Phase II Study PRVM Cohort, patients with PIK3CA mutation confirmed by local laboratory test may proceed to clinical screening but must provide fresh or archived tissue samples, and enrollment is permitted only after central laboratory confirmation of PIK3CA mutation), with at least one measurable lesion related to PROS or PRVM. For the Phase II Study, measurable lesions must be confirmed by central imaging assessment before patients can be enrolled
a)The diagnosis of PROS should meet the clinical diagnostic criteria, such as Klippel-Trenaunay syndrome (KTS), CLOVES syndrome, CLAPO syndrome, diffuse capillary malformation with overgrowth (DCMO), megalencephaly-capillary malformation (MCAP), hemihyperplasia-multiple lipomatosis (HHML), fibroadipose vascular anomaly (FAVA), facial infiltrating lipomatosis (FIL), fibroadipose hyperplasia or overgrowth (FAO), or other PROS subtypes, and should be determined by the investigator to require systemic treatment;
b) PRVM should meet one of the following clinical diagnostic types, simple vascular malformations, such as lymphatic malformation (LM), venous malformation (VM), combined vascular malformations, such as capillary-venous malformation (CVM), capillary-lymphatic malformation (CLM), lymphatic-venous malformation (LVM), capillary-lymphatic-venous malformation (CLVM), or other vascular malformations, and should be determined by the investigator to require systemic treatment.
The criteria for requiring systemic treatment as determined by the investigator are as follows (both conditions must be met),
1)Clinical symptoms: Accompanied by complaints, clinical symptoms or functional limitations affecting the patient's daily life (e.g., pain, fatigue, inability to walk normally, etc.)
2)Treatment options, The patient is unsuitable or unwilling to undergo conventional treatments such as surgery, sclerotherapy, or interventional therapy, or has experienced treatment failure/relapse after receiving these therapies.

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 (including surgery, sclerotherapy, laser therapy, interventional therapy, local injection therapy, etc.) within 8 weeks prior to the first dose of study drug, or any drug treatment for PROS or PRVM (e.g., mTOR inhibitors, AKT inhibitors) within 28 days prior to the first dose of study drug, or who have not recovered from the serious side effects.
3. Patients who have previously received any PI3K inhibitor (e.g., alpelisib) treatment. If the efficacy of previous PI3K inhibitor treatment was inadequate for reasons other than disease progression, eligibility for enrollment may be determined after evaluation by the investigator.
4. Clinically significant PROS/PRVM-related thrombotic events (>=Grade 2, according to NCI-CTCAE v5.0) occurring within 8 weeks prior to signing the informed consent form, and/or sclerotherapy/embolization for vascular complications within 8 weeks prior to signing the informed consent form. Patients receiving anticoagulants for the treatment of PROS/PRVM related coagulation disorders and primary or secondary prevention of thrombosis may be enrolled in the study.
5. Patients who have received blood transfusion or platelet infusion therapy within 2 weeks prior to study drug administration. Patients who have been receiving erythropoietin or darbepoetin treatment at least 2 weeks prior to enrollment may be included and allowed to continue such treatment.

Both

PIK3CA-Related Overgrowth Spectrum (PROS) and PIK3CA-Related Vascular Malformations (PRVM)

For the Phase II PROS cohort of this study, the starting dose is CYH33 10 mg QD. After at least 8 weeks of treatment, dose escalation to 15 mg QD will be permitted based on the investigators assessment of the patients benefit and risk. For the Phase II PRVM cohort of this study, the dosing regimen is CYH33 10 mg QD. Additionally, dose reduction will be permitted for patients in both Phase I and Phase II who cannot tolerate the assigned treatment dose.

Oral administration

D054079

D000284

Blinded Independent Review Committee assessed response rate at Week 24 (defined as >=20% reduction from baseline in the sum of target lesion volumes with no progression of non target lesions and no new lesions)

Key Secondary Endpoint
/Blinded Independent Review Committee assessed response rate at Week 48
Secondary Endpoint
/Blinded Independent Review Committee assessed response rate at Week 8, double blind period, in PRVM cohort
/Blinded Independent Review Committee assessed response rates at Weeks 8 and 16
/Change from baseline as assessed by Blinded Independent Review Committee in the sum of target lesion volume
/Overall clinical response as assessed by Investigator
/Changes from baseline in PROMIS, and EQ5D5L recorded in PRO diaries
/Type, incidence, and severity of AEs assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0, and safety evaluation results, e.g., changes in physical examination, laboratory test data, Karnofsky or Lansky performance status, vital signs, and electrocardiogram, etc.
/Plasma drug concentrations of CYH33 and its metabolite I27

Nov. 27, 2025

Nov. 27, 2025

Nov. 27, 2025

Nov. 27, 2025

Nov. 27, 2025

Nov. 27, 2025

Nov. 27, 2025

No

China