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)

Eligibility criteria

Study arms

• Experimental
  Arm 1：Adult cohort:；

  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

• Experimental
  Arm 2: Phase I Adolescent Cohort

  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

• Experimental
  Arm 3 : Phase II PROS Cohort

  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

• Experimental
  Arm 4 : Phase II PRVM Cohort

  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

• DrugCYH33

  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.

• DrugPlacebo

  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 outcomes

1. 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

2. 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

3. 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).

   Time frame: Baseline to 24weeks

Secondary outcomes

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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)