A Phase I Study of SY-9453 in Patients With Advanced Solid Tumors

An Open-label, Multi-center, Dose-escalation and Dose-expansion Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of SY-9453 in Patients With Advanced Solid Tumors

This is an open-label, single-arm, multicenter, dose-escalation and dose-expansion, phase I study to the safety, tolerability, pharmacokinetics, and preliminary efficacy of SY-9453 in patients with advanced solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced or Metastatic Solid Tumors With Homozygous MTAP Deletion
• Intervention / Treatment: Drug: SY-9453

Detailed Description

The study will be conducted in 2 parts:

Dose-escalation phase: Participants will be allocated to one of the seven dose groups ranging from 5mg to 80mg and receive a single dose of SY-9453 capsules.This phase is designed to determine the DLTs (Dose-limiting toxicity) and recommended phase II dose (RP2D) and characterize the safety, tolerability and PK of SY-9453 in patients with advanced solid tumors.

Dose-expansion phase: Based on the recommended doses (RDEs) obtained in the escalation phase (possibly 1-2 doses), a dose expansion study will be conducted in 1-3 MTAP homozygous deletion advanced or metastatic solid tumor cohorts, with 10-20 patients per dose in each cohort to further evaluate the safety, tolerability, PK characteristics and anti-tumor activity of SY-9453 to clarify RP2D.

• Study Type: Interventional
• Enrollment (Estimated): 122
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: chen guang wang; Phone Number: 010-8885-8866; Email: cgwang@centaurusbio.com

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Shanghai East Hospital
    • Contact: caicun zhou; Email: caicunzhoudr@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for this study:

1. Subjects voluntarily participated in this study and signed the written informed consent (ICF);
2. Age ≥ 18 years at the time of signing the Informed Consent Form (ICF);
3. Histologically or cytologically confirmed locally advanced solid tumor and disease progression or intolerance after adequate standard treatment, or lack of standard treatment options.

For subjects participating in the dose escalation phase (only for dose groups of 30 mg and above) and the dose expansion phase: be able to provide a previous test report confirmed by NGS or IHC to be homozygous deletion of the MTAP gene approved by the investigator, or agree to provide sufficient archived or baseline tumor tissue samples, confirmed to be homozygous deletion of the MTAP gene by central laboratory testing.

4.At least one measurable extracranial lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria or mRECIST V1.1（Mesothelioma subjects only）(subjects participating in accelerated titration phase are not required to meet this requirement).

5.Expected survival of >3 months. 6.Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1. 7.Organ function levels must meet the following requirements:

1. No blood products, hematopoietic growth factors (e.g., G-CSF, thrombopoietin, erythropoietin, platelet transfusion, whole blood transfusion, red blood cell transfusion), or other drugs that correct abnormal blood counts for at 14 days before first dosing and the following blood counts: ANC ≥ 1.5 × 10^9/L, PLT count ≥ 100 × 10^9/L, Hb ≥ 90 g/L.
2. Renal function: Creatinine clearance (Ccr) ≥ 60 mL/min (calculated using the Cockcroft and Gault formula).
3. Liver function: TBIL ≤ 1.5 × upper limit of normal (ULN), and AST and ALT ≤ 2.5 × ULN; in the presence of liver metastases, AST and ALT ≤ 5.0 × ULN, and serum albumin ≥ 30 g/L.
4. Coagulation function: Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN, and International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN (except for patients receiving anticoagulant therapy).

8.Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the first dose, male and female patients of childbearing potential must be willing to completely abstain or agree to use an appropriate method of contraception during the entire study duration and for at least 3 months after the last dose of study medication.

Exclusion Criteria:

1. Patients previously treated with a MAT2A inhibitor or PRMT5 inhibitor. 2. History of allergy to any component or excipient of SY-9453 capsules. 3. Received the following treatments prior to the first dose:

1. Small-molecule targeted drugs within 2 weeks(or 5 half-lives, whichever is shorter).
2. Hormonal anti-tumor therapy within 2 weeks or as judged by the investigator.
3. Chinese herbal medicine or preparations with indications for anti-tumor therapy or tumor adjuvant therapy within 2 weeks or as judged by the investigator.
4. Radiotherapy within 4 weeks (with 2 weeks if the radiotherapy was palliative stereotactic radiotherapy that did not involve the lungs, abdomen and pelvis)
5. Chemotherapy: fluorouracil, leucovorin, and/or weekly paclitaxel with 2 weeks; nitrosourea or mitomycin C with 6 weeks; other chemotherapy with 3 weeks.
6. Other investigational drugs with 4 weeks.
7. Biotherapy within 4 weeks(or 5 half-lives, whichever is longer)
8. Immunotherapy within 4 weeks.
9. Major surgery within 4 weeks (excluding central venous catheter insertion, bone marrow biopsy and gastric tube insertion).
10. Radioactive Particle Therapy within 3 months.
11. Radionuclide therapy within 3 months.
12. Autotransplantation (including CAR-T therapy and other similar treatments) within 3 months.

4.Adverse events from prior anti-cancer therapies have not recovered to Grade ≤1 as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 (except for toxicities assessed by the investigator as posing no safety risk, such as alopecia and Grade 2 peripheral neuropathy).

5.Other malignancies within 3 years before screening, with the following exceptions: cured cervical carcinoma in situ, squamous cell carcinoma of the skin, and cured basal cell carcinoma(except for the subjects participating in accelerated titration phase).

6.Dysphagia, or presence of a gastrointestinal disorder or other malabsorption condition that affects drug absorption, such as intestinal obstruction, Crohn's disease, ulcerative colitis, severe peptic ulcer, gastrointestinal perforation, or acute gastrointestinal bleeding.

7. Presence of active central nervous system (CNS) disease (if the clinical performance is stable assessed by the investigator at least 4 weeks before the first dose of SY-9453, and steroid treatment has been discontinued for ≥14 days, the patients can be included.

8.Hepatitis B during screening (positive results for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb] with HBV-DNA ≥1000 IU/mL; patients whose HBV-DNA levels drop to below 1000 IU/mL after regular antiviral treatment can be included), or active hepatitis C (HCV RNA > central detection upper limit of normal [ULN]), active syphilis (positive for both Treponema pallidum-specific and non-specific antibodies); history of tuberculosis (evidence of active tuberculosis infection within 1 year), Human immunodeficiency virus (HIV) positive during screening, or known history of other immunodeficiency diseases.

9.Presence of other underlying medical conditions as assessed by the investigator may put the subject at risk or affect the assessment of the toxicity of SY-9453 or AEs.

10. History of neurological or mental disorders, such as dementia. 11. Presence of the following clinically significant comorbidities, including but not limited to:

1. .Left ventricular ejection fraction (LVEF) ≤ 50%.
2. . Heart failure, myocardial infarction, unstable angina with 6 months, or classified as New York Heart Association (NYHA) class II, III or IV congestive heart failure.
3. . High-risk uncontrolled arrhythmias within 6 months: atrial tachycardia with a resting heart rate >100 beats/min, significant ventricular arrhythmias (such as ventricular tachycardia), or high-grade atrioventricular block (such as type II second-degree or third-degree atrioventricular block).
4. .History of Percutaneous Transluminal Coronary Angioplasty (PTCA) or stent implantation within 6 months.
5. . Aortic stenosis.
6. . Fridericia-corrected QT interval (QTcF) > 470 msec (females) or 450 msec (males) at baseline (if QTcF prolongation suspected to be drug-induced is assessed as safe and controllable by the investigator, the patient can be included after correction with medication).
7. .Poorly controlled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110mmHg) or diabetes (fasting blood glucose ≥ 11.1mmol/L and/or HbA1c ≥ 8%).
8. .Clinically significant active infection requiring systemic antibiotic, antiviral, or antifungal therapy.
9. .Serous cavity effusion, or pleural effusion, ascites, or pericardial effusion poorly controlled after intervention (poorly controlled indicates significant increase in effusion within 2 weeks after drainage, with significant symptoms requiring re-puncture or other interventions).
10. Stroke occurred within 6 months before screening. Evidence of central nervous system bleeding on baseline MRI or CT scan (subject had asymptomatic grade 1 bleeding stable for less than 3 months postoperatively).
11. . Presence of drug-resistant seizures.
12. .Severe lung diseases, including but not limited to pulmonary embolism, severe asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, or active pneumonia or interstitial pneumonia that occurred 3 months before signing the notification, and pulmonary function tests indicate severe impairment of lung function.

12. History of allogeneic organ transplantation or allogeneic peripheral blood stem cell transplantation (allo-HSCT)/bone marrow transplantation.

13. Use of or inability to stop using the following CYP3A4 potent inhibitors or inducers within 2 weeks before the first dose during the study.

14. Pregnancy or breastfeeding women. 15. Other situations deemed unsuitable for participation in this clinical trial by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose-escalation and Dose-expansion; In dose-escalation phase, SY-9453 will be given orally in ascending doses (escalation cohort) until the DLT or Recommended doses（RDEs) is reached. In dose-expansion phase, SY-9453 will be given orally in RDEs (possibly 1-2 doses) for the expansion period based on the escalation phase in 28-day cycle continuously.	Drug: SY-9453; Dose-escalation phase: Multiple doses of SY-9453 for oral administration ranging from 5mg to 80mg. Dose-expansion phase: RDEs of SY-5007 asdetermined during Dose Escalation.; Other Names: SY-9453 capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of adverse events (AEs)	Characterization of the safety and tolerability	Up to 3 years
Incidence of dose limiting toxicities (DLTs)	Characterization of the safety and tolerability	Escalation phase (35 days after the first dose)
Number of Participants With Abnormal Laboratory Values	Characterization of the safety and tolerability	up to 3 years
Recommended Phase II Doses (RP2D) of SY-9453		Up to 2 years
Maximum tolerated dose of SY-9453 (if applicable)	Characterization of the safety and tolerability	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		up to 3 years
Pharmacokinetics (Cmax) for SY-9453	Defined as maximum observed plasma concentration	At the end of Cycle 1 (each cycle is 28 days)
Pharmacokinetics (Tmax) for SY-9453	Defined as time to maximum plasma concentration	At the end of Cycle 1 (each cycle is 28 days)
Pharmacokinetics (AUC0-t) for SY-9453	Defined as area under the single-dose plasma concentration-time curve from Hour 0 to the last quantifiable measurable plasma concentration	At the end of Cycle 1 (each cycle is 28 days)
Pharmacokinetics (t½) for SY-9453	Defined as the apparent plasma terminal phase disposition half-life	At the end of Cycle 1 (each cycle is 28 days)
Overall Response Rate (ORR) assessed by RECIST v1.1	Preliminary anti-tumor activity of SY-9453	Up to 3 years
Disease control rate (DCR) as assessed by RECIST v1.1	Preliminary anti-tumor activity of SY-9453	Up to 3 years
Duration of response (DOR) as assessed by RECIST v1.1	Preliminary anti-tumor activity of SY-9453	up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum symmetric dimethylarginine (SDMA) from baseline	Biomarkers related to the efficacy of SY-9453 (if applicable)	up to 3 years
Changes in ctDNA from baseline		up to 3 years
The incidence of adverse events related to QTcF prolongation	Explore the effect of SY-9453 on QTcF	At the end of Cycle 1 (each cycle is 28 days)
The correlation between QTcF prolongation and SY-9453 plasma concentration		At the end of Cycle 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Shouyao Holdings (Beijing) Co. LTD
• Collaborators: Shanghai East Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: March 3, 2026
• First Submitted That Met QC Criteria: March 12, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: MTAP
• Other Study ID Numbers: SY-9453-I-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No