Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HLX97 (a KAT6A/B Inhibitor) in Patients With Advanced/Metastatic Solid Tumor

Inclusion criteria

• Subjects must voluntarily agree to participate in the trial and sign a written informed consent form;
• 18-80 years of age, either sex;
• Subjects who meet the corresponding requirements below will be enrolled.

• Part 1A will enroll subjects with histologically or cytologically confirmed advanced/metastatic HR-positive, HER2-negative breast cancer (BC), castration-resistant prostate cancer (CRPC), or non-small cell lung cancer (NSCLC) who have failed standard therapy or for whom no standard therapy exists.
• Part 1B will enroll subjects with histologically or cytologically confirmed advanced or metastatic HR-positive, HER2-negative breast cancer.
• Part 2 will enroll subjects with histologically or cytologically confirmed advanced or metastatic HR-positive, HER2-negative breast cancer.
• ECOG performance status of 0-1;
• Life expectancy ≥ 12 weeks;
• Adequate bone marrow and organ function.

Exclusion criteria

• History of any second malignancy within 3 years prior to signing the ICF. Exceptions include early-stage malignancies (carcinoma in situ or Stage I tumors) that have been curatively treated, such as non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, or papillary thyroid cancer.

Active systemic infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to the first dose.

Subjects with poorly controlled clinical symptoms or diseases of the cardiovascular and cerebrovascular system, including but not limited to:

NYHA Class ≥II heart failure or left ventricular ejection fraction (LVEF) < 50%; Unstable angina; Myocardial infarction or cerebrovascular accident within 6 months (excluding lacunar infarction, minor cerebral ischemia, or transient ischemic attack); Poorly controlled arrhythmias (including QTc interval ≥450 ms for males or ≥470 ms for females, calculated using the Fridericia formula); Poorly controlled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg despite active treatment).

Presence of spinal cord compression or clinically symptomatic central nervous system (CNS) metastases, defined as untreated, symptomatic, or requiring corticosteroids or anticonvulsants to control symptoms. Subjects with stable brain metastases may be included. Subjects with previously diagnosed brain metastases are eligible if they have completed treatment, have recovered from the acute effects of radiotherapy or surgery prior to enrollment, have discontinued corticosteroid therapy for these metastases for at least 3 weeks, and are neurologically stable for 2 months (requiring MRI confirmation).

Presence of residual toxicity from prior anti-tumor therapy that has not resolved, defined as toxicity not resolved to Grade ≤1 or baseline levels per CTCAE V5.0 (alopecia excepted).

Note: Subjects with chronic, stable Grade 2 toxicity deemed by the investigator to be related to prior anti-tumor therapy (defined as no worsening to ≥ Grade 2 for at least 3 months prior to enrollment and managed with standard medical measures) may be enrolled; for example: chemotherapy-induced neuropathy, fatigue, and residual toxicity from prior immunotherapy (Grade 1 or 2 endocrinopathies, which may include hypothyroidism/hyperthyroidism, Type 1 diabetes mellitus, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation/vitiligo).

Prior radiotherapy to bone marrow involving >25% of the total bone marrow volume (e.g., prior whole pelvic radiotherapy, whole spine radiotherapy, etc.; excluding local radiotherapy to single or a few vertebral bodies, local radiotherapy to the chest wall, etc.).

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (defined as requiring drainage at least once monthly).

Use of therapeutic anticoagulants. Low molecular weight heparin is permitted. Use of vitamin K antagonists or Factor Xa inhibitors may be permitted after discussion with the sponsor.

Active inflammatory gastrointestinal disease, refractory or unresolved chronic diarrhea, or history of gastrectomy, gastric banding surgery, or other gastrointestinal conditions or surgeries that could significantly alter the absorption of HLX97 tablets. Treated gastroesophageal reflux disease is permitted.

Patients who received systemic corticosteroids (prednisone ≥10 mg/day or equivalent dose of similar medication) or other immunosuppressive agents within 14 days prior to the first dose.

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