A Phase I/II Study of FWD1802 in Patients With ER+/HER2- Advanced BC.

Exclusion Criteria

• •Subjects meeting any of the following criteria will be excluded from the study:
• •1. Leptomeningeal metastases, carcinomatous meningitis, spinal cord compression, or symptomatic or clinically unstable central nervous system (CNS) metastases.
• •2. History of ongoing gastrointestinal diseases or other malabsorptive conditions that may impact the absorption of orally administered study drugs, including but not limited to:
• •1. Inability to swallow oral medications.
• •2. Requirement for intravenous nutrition.
• •3. Prior surgery affecting absorption, including total/partial gastrectomy.
• •4. Crohn's disease, ulcerative colitis.
• •5. Treatment for active peptic ulcer disease within 6 months prior to the first dose.
• •6. Malabsorption syndrome, or uncontrolled nausea, vomiting, or diarrhea.
• •3. Patients with symptomatic visceral metastases, or those with clinically significant and unstable pleural, peritoneal, pericardial effusions, or pulmonary lymphangitic carcinomatosis. Patients who have received intracavitary infusion therapy or drainage/paracentesis may be enrolled 14 days or more after the effusion has stabilized. Other conditions deemed by the investigator as unsuitable for endocrine therapy.
• •4. Prior treatments do not meet the following washout periods:
• •1. Use of other investigational drugs or devices within 4 weeks prior to the first dose.
• •2. Treatment with CDK4/6 inhibitors or mTOR inhibitors within 2 weeks, or other targeted therapies, chemotherapy, or immunotherapy within 4 weeks prior to the first dose.
• •3. Radiotherapy, endocrine drugs, or traditional Chinese medicines with anti-tumor indications within 2 weeks prior to the first dose (washout periods for fulvestrant and tamoxifen refer to Inclusion Criterion 7).
• •4. Treatment with mitomycin or nitrosoureas within 6 weeks prior to the first dose.
• •5. Use of drugs or herbal supplements known to be moderate/strong inhibitors or inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).
• •6. Use of drugs that inhibit gastric acid production within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).
• •7. Use of drugs that are P-glycoprotein (P-gp) inhibitors within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose (see Appendix 4).
• •5. Toxicities from prior anti-tumor therapy have not recovered to Grade ≤1 (except for alopecia, and chemotherapy-induced peripheral neuropathy ≤ Grade 2).
• •6. Major surgical procedure (excluding biopsy) within 4 weeks prior to the first dose of study drug, or incomplete healing of surgical incision.
• •7. Known other active malignancy within the past 5 years (except for cured basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, papillary thyroid carcinoma, or ductal carcinoma in situ of the breast).
• •8. History of interstitial lung disease, drug-induced interstitial lung disease, or any evidence of active pneumonitis on chest CT scan within 4 weeks prior to the first dose of study drug.
• •9. Poorly controlled hypertension despite antihypertensive therapy (systolic blood pressure \>150 mmHg or diastolic blood pressure \>95 mmHg).
• •10. Active hepatitis B (defined as HBsAg positive and HBV DNA \>500 IU/mL or \>2000 copies/mL, or HBV DNA above the lower limit of detection if the local lower limit is \>500 IU/mL or \>2000 copies/mL); hepatitis C virus (HCV) infection (defined as HCV antibody positive and HCV-RNA positive or HCV-RNA above the lower limit of detection at the local site).
• •Known HIV infection or history of acquired immunodeficiency syndrome (AIDS); active tuberculosis; active syphilis infection.
• •11. Any severe infection requiring systemic antibiotics within 14 days prior to dosing, or active infection requiring systemic treatment.
• •12. Arterial or venous thrombotic events within 6 months, including cerebrovascular accident (e.g., transient ischemic attack, cerebral hemorrhage, etc.), deep vein thrombosis, or pulmonary embolism.
• •13. History of active cardiac disease or cardiac dysfunction, including any of the following:
• •1. Idiopathic symptomatic bradycardia within 2 years prior to screening, or resting heart rate \<50 bpm at screening.
• •2. History of angina or symptomatic coronary artery disease within 1 year prior to screening.
• •3. History of congestive heart failure (NYHA Class ≥3), cardiomyopathy, or myocardial ischemia requiring long-term medication for control.
• •4. Acute myocardial infarction event within 6 months prior to screening.
• •5. History of ventricular arrhythmia, or any supraventricular arrhythmia ≥ Grade 2 requiring treatment or intervention within 1 year prior to screening, or presence of risk factors for ventricular arrhythmias.
• •6. Any factors that increase the risk of QTc prolongation or arrhythmic events, such as symptomatic heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under age 40 in a first-degree relative. Hypertrophic cardiomyopathy and clinically significant valvular stenosis.
• •7. Poorly controlled atrial fibrillation, history of coronary/peripheral artery bypass graft within the past 6 months, or cerebrovascular symptoms including transient ischemic attack.
• •8. QTcF (Fridericia's correction) \> 470 ms on ECG.
• •9. Presence of ECG abnormalities considered clinically significant by the investigator, including complete left bundle branch block, second- or third-degree heart block, or sick sinus syndrome.
• •14. History of severe allergic reactions to the study drug(s) or excipients used in the protocol.
• •15. Prior use of any selective estrogen receptor degrader (other than fulvestrant) or investigational drugs inhibiting the ER signaling pathway.
• •16. Patients with active or chronic corneal disease, other active eye disease requiring ongoing treatment, or any clinically significant corneal disease for which drug-induced keratopathy cannot be adequately monitored.
• •17. History of drug abuse, alcohol abuse, or substance abuse.
• •18. Use of live or attenuated live vaccines within 4 weeks prior to the first dose of study drug. Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferon, etc., within 14 days prior to the first dose of study drug. History of allogeneic organ transplantation, allogeneic peripheral hematopoietic stem cell transplantation, or bone marrow transplantation.
• •19. Conditions deemed by the investigator as unsuitable for participation in this study, including but not limited to a clear history of neurological disorders such as epilepsy or dementia, poor compliance, or any other circumstances the investigator believes may render the subject unsuitable for the study.