SYH2095 for Advanced Malignant Tumors: Phase I Study

Official title

An Open-Label, Multi-Center Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SYH2095 in Advanced Malignant Tumors

Overview

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.

Interventions

• Drug SYH2095
  Selective KAT6A/B inhibitor, oral tablet.. Administered orally once daily on an empty stomach, 4 weeks per treatment cycle.

Primary outcome measures

• Incidence of Dose-Limiting Toxicity [Time frame: End of Part 1 Dose Escalation and Backfill phase (each cycle is 28 days; all safety data collected through Day 28 of Cycle 1 for every dose-escalation subject)]]
• Maximum Tolerated Dose (MTD) of SYH2095 [Time frame: End of Part 1 Dose Escalation and Backfill phase (each cycle is 28 days; all safety data collected through Day 28 of Cycle 1 for every dose-escalation subject)]]
• Maximum Tolerated Dose of SYH2095 [Time frame: End of Part 1 Dose Escalation phase (each cycle is 28 days; safety data collected through Day 28 of Cycle 1 for all dose-escalation subjects)]]
• Objective Response Rate [Time frame: 2 years]
• Phase 2 Recommended Dose of SYH2095 [Time frame: 2 years]
• Overall Safety Profile [Time frame: From informed consent to 28 days after last study drug administration]
• Maximum Observed Concentration (Cmax) [Time frame: 2 years]

Secondary outcome measures (11)

• Time to Maximum concentration (Tmax) [Time frame: 2 years]
• AUC from time zero to time of last measurable concentration (AUClast) [Time frame: 2 years]
• Terminal Elimination half-life (t1/2) [Time frame: 2 years]
• Steady-State Cmax [Time frame: 2 years]
• Steady-state Tmax (Tmax,ss) [Time frame: 2 years]
• Steady state AUC during a dosage interval (τ) (AUCτ,ss) [Time frame: 2 years]
• Steady-state apparent total clearance (CLss/F) [Time frame: 2 years]
• Progression Free Survival (PFS) [Time frame: 2 years]
• Overall survival (OS) [Time frame: 2 years]
• Duration of Response (DOR) [Time frame: 2 years]
• Disease Control Rate (DCR) [Time frame: 2years]

Eligibility criteria

Inclusion criteria

• Fully understand this clinical trial, and voluntarily sign a written informed consent form (ICF);
• Age ≥ 18 years (at the time of informed consent), male or female;
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 0-1;
• Estimated life expectancy ≥ 3 months;
• At least one measurable or evaluable tumor lesion at baseline per RECIST V1.1;
• For advanced HR+/HER2- breast cancer, the following requirements must be met:

• 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%;
• 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 <2.0, or HER2 gene copy number <4.0 using a single probe);
• Participants need to be postmenopausal. Female participants with childbearing potential (or have tubal ligations only) must be willing to undergo medically induced menopause by treatment with the approved LHRH agonist such as goserelin, leuprolide, or an equivalent to induce chemical menopause.7.Participants with childbearing potential (male or female) must agree to use a reliable contraceptive method (see Appendix 13.1) with their partner during trial and for at least 13 weeks (males) or 25 weeks (females) after the last dose. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose;

8.Participants must meet the following laboratory tests requirements (all test results must be completed within 7 days before the first dose without corrective interventions such as transfusion, hematopoietic growth factors, etc., or stable for more than 7 days after treatment)

Exclusion criteria

• Presence of known active Central Nervous System (CNS) metastases and/or carcinomatous meningitis. Participants with prior locoregional treatment for brain metastases may be enrolled only if medically stable for ≥ 4 weeks prior to the first dose. Medically stable is defined as the following conditions: no clinical symptoms attributable to CNS metastases within 4 weeks prior to the first dose (e.g., progressive or new neurological deficit, epileptic seizure, increased intracranial pressure, vomiting, papilledema, or headache); no evidence of CNS neoplasm relapse/progression on imaging assessments within 4 weeks prior to the first dose; no glucocorticoid therapy (>10 mg/day prednisone or equivalent) for ≥4 weeks prior to the first dose;
• Participants with uncontrolled third interstitial effusions (e.g., pericardial effusion, pleural effusion, ascites) that cannot be controlled by repeated drainage or other interventions, and who are not suitable for enrollment by the investigator;
• Participants with history of severe cardiovascular disease within 6 months prior to the first dose, including any of the following: (1) Congestive heart failure (New York Heart Association (NYHA) class > 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;
• 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.);
• 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);
• 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.);
• 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;

• 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);
• Use of strong/moderate inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose;
• Use of proton pump inhibitors (PPIs) within 2 weeks prior to the first dose;
• 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;
• 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;
• 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.);
• Previous participation in any clinical trial involving a KAT6A/B or KAT7 inhibitor;
• Hypersensitivity to any investigational product or its excipients in this clinical trial;
• Female participants who are pregnant, breastfeeding, or planning a pregnancy during the trial;
• 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);
• Participants with hemorrhagic events within 4 weeks prior to the first dose (e.g., active gastrointestinal bleeding, gross hematuria, haemoptysis, etc.);
• 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;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 1 center

• Tianjin Medical University Cancer Institute and Hospital — Tianjin

Identifiers

NCT: NCT07692776 · SYH2095-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗