SYH2095 for Advanced Malignant Tumors: Phase I Study

This is an open-label, multicenter Phase 1 first-in-human trial of SYH2095, a selective KAT6A/B inhibitor. The trail contains two segments: Part 1A dose escalation and Part 2A cohort expansion. Part 1A uses the BOIN dose-escalation design, enrolling patients with advanced malignant tumors with no effective standard treatment. Its primary goals are to assess safety and tolerability, define dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), and establish the recommended expansion dose (RDE). Part 2A is an expansion cohort using the RDE identified in Part 1A,. All participants receive oral SYH2095 once daily in 4-week treatment cycles. Safety evaluations, tumor imaging, pharmacokinetic (PK), pharmacodynamic (PD) and biomarker analyses will be performed at scheduled time points throughout treatment.

Inclusion Criteria: 1. Fully understand this clinical trial, and voluntarily sign a written informed consent form (ICF); 2. Age ≥ 18 years (at the time of informed consent), male or female; 3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 0-1; 4. Estimated life expectancy ≥ 3 months; 5. At least one measurable or evaluable tumor lesion at baseline per RECIST V1.1; 6. For advanced HR+/HER2- breast cancer, the following requirements must be met: 1. HR positive is defined as: ER positive and/or PR positive, confirmed by tumor biopsy (biopsy method comply with local diagnosis and treatment standards) that the tumor tissue is ER/PR positive, and the proportion of positive staining cells among all tumor cells is ≥1%; 2. HER2 negative is defined based on American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as: immunohistochemistry score of 0/1+, or a negative result determined by in situ hybridization (HER2/CEP17 ratio \ grade Ⅱ); (2) Severe/unstable angina, or new-onset angina pectoris within 3 months before the first dose; (3) Participants with myocardial ischaemia requiring long-term pharmacologic control, or heart failure (NYHA class Ⅲ-Ⅳ); (4) History of acute myocardial infarction; (5) Any grade ≥2 supraventricular or ventricular arrhythmia requiring treatment or intervention; (6) History of atrial fibrillation, coronary/peripheral artery bypass grafting, or transient ischaemic attack (TIA) with cerebrovascular symptoms; (7) Uncontrolled hypertension at screening (despite pharmacotherapy: diastolic blood pressure ≥ 100 mmHg and/or systolic blood pressure ≥ 160 mmHg);(8) QTcF≥ 470 ms on 12-lead (ECGs) performed in triplicate; 4. Participants with factors affecting oral administration (e.g., dysphagia, intestinal obstruction); or active gastrointestinal diseases or other conditions that may significantly alter drug absorption, distribution, metabolism, or excretion (including active inflammatory bowel disease, chronic diarrhea, frequent vomiting, enterocolitis, etc.); 5. Participants with active autoimmune disease, a history of immunodeficiency or autoimmune disease, or a history of non-active autoimmune disease requiring long-term treatment with systemic corticosteroids or immunosuppressants agents, or with conditions associated with immunodeficiency (including HIV, congenital immunodeficiency diseases, etc.), or a history of organ transplantation (including allogeneic bone marrow transplantation); 6. Drug-induced pneumonia, interstitial lung disease (ILD), or immune-mediated pneumonitis; or a history of active radiation pneumonitis requiring steroid therapy, or other severe lung dysfunction diseases, symptoms or signs at screening (e.g., severe chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, etc.); 7. Presence of active hepatitis B, active hepatitis C, active tuberculosis, or active syphilis infection, including: A. Active hepatitis B: HBsAg positive and HBV-DNA quantitative titer test ≥20 IU/mL or HBV-DNA ≥102; B. Active Hepatitis C: anti-HCV positive and HCV-RNA positive; C. Active tuberculosis: history of tuberculosis treatment within 2 years prior to the first dose; D. Active syphilis: presence of syphilis infection requiring systemic therapy; 8. Participants with a diagnosis of other malignant tumor within the past 5 years (except those with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, papillary thyroid carcinoma, or carcinoma in situ \[e.g., cervical carcinoma in situ, breast ductal carcinoma in situ\] that have received radical treatment); 9. Use of strong/moderate inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose; 10. Use of proton pump inhibitors (PPIs) within 2 weeks prior to the first dose; 11. History of nervous system or psychiatric disorders, history of psychotropic drug abuse, or drug addiction ; alcohol or drug abuse/dependence, which may interfere with the administration of the investigational product, affect the assessment and judgment of investigational product's toxicity and AEs, or result in inadequate or decreased trial compliance; participants with other severe physical or laboratory abnormalities that, in the investigator's judgment, may increase the risk to the participant or interfere with the clinical trial results, and are thus considered unsuitable for trial participation; 12. Received any anti-tumor therapy or enrolled in other interventional clinical trial within 4 weeks prior to the first dose, including cytotoxic drugs, endocrine therapy, immunotherapy, targeted therapy, surgery (except puncture biopsy, peripherally inserted central catheterisation or infusion port catheterization) or other clinical trial investigational products; or received radiotherapy within 2 weeks prior to the first dose; 13. Previous anti-tumor therapy-related toxicity that has not recovered to CTCAE version 6.0 grade ≤1 (except toxicities determined by the investigator to post no safety risk, e.g., alopecia, fatigue, isolated laboratory abnormalities, peripheral neuropathy, etc.); 14. Previous participation in any clinical trial involving a KAT6A/B or KAT7 inhibitor; 15. Hypersensitivity to any investigational product or its excipients in this clinical trial; 16. Female participants who are pregnant, breastfeeding, or planning a pregnancy during the trial; 17. Participants with active infection requiring treatment with antibiotics, antivirals or antifungals, or unexplained fever \>38.5℃ within 2 weeks prior to the first dose (except tumor-related fever as determined by the investigator); 18. Participants with hemorrhagic events within 4 weeks prior to the first dose (e.g., active gastrointestinal bleeding, gross hematuria, haemoptysis, etc.); 19. Presence of severe bone injury due to bone metastases, as determined by the investigator, including uncontrolled severe bone pain, pathological fractures at critical sites, or spinal cord compression that occurred within 6 months prior to the first dose or is expected to occur in the near future;