SY-9453 for advanced solid tumors with homozygous MTAP deletion

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 trial will test whether the oral drug SY-9453 is safe and shows anti-tumor activity in adults with advanced or metastatic solid tumors that have a homozygous MTAP deletion.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 122 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Shouyao Holdings (Beijing) Co. LTD (Academic / other)
• Drugs / interventions: CAR-T, Chemotherapy, Immunotherapy
• Locations: 1 site (Shanghai)
• Trial ID: NCT07469982 on ClinicalTrials.gov

What this trial studies

This open-label, single-arm, multicenter Phase 1 program uses a dose-escalation then dose-expansion design to characterize safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of SY-9453. In the escalation phase participants are assigned to one of seven dose cohorts (5 mg to 80 mg) to identify dose-limiting toxicities (DLTs) and a recommended phase II dose. The expansion phase will enroll 1–3 cohorts of MTAP homozygous-deleted advanced or metastatic solid tumors (approximately 10–20 patients per dose cohort) using the recommended dose(s) from escalation to further define safety, PK, and anti-tumor signals. Serial tumor and blood sampling will be used for PK and correlative analyses, and tumor response will be measured using RECIST criteria.

Who should consider this trial

Good fit: Adults (≥18) with histologically or cytologically confirmed advanced or metastatic solid tumors who have progressed after standard therapies and whose tumors are confirmed to have a homozygous MTAP deletion (required for expansion and higher-dose escalation cohorts) are the intended participants.

Not a fit: Patients whose tumors do not have a homozygous MTAP deletion or who are medically unfit for investigational therapy (for example, poor organ function or rapidly progressive disease) are unlikely to receive benefit from this targeted agent.

Why it matters

Potential benefit: If successful, SY-9453 could provide a new targeted treatment option for patients with MTAP-deleted advanced solid tumors.

How similar studies have performed: Related approaches targeting vulnerabilities in MTAP-deleted tumors (for example MAT2A/PRMT5 pathway inhibitors) have shown early clinical signals but remain investigational and not yet proven in larger trials.

Eligibility criteria

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.

Where this trial is running

Shanghai

• Shanghai East Hospital — Shanghai, China (Recruiting)

Study contacts

• Study coordinator: chen guang wang

Conditions Advanced or Metastatic Solid Tumors With Homozygous MTAP Deletion; MTAP