A Phase II Clinical Study of Utidelone and Bevacizumab With or Without Etoposide in Patients With Brain Metastases From Malignant Solid Tumors

Inclusion Criteria:

• Subjects must provide informed consent for the trial and voluntarily sign the written informed consent form (ICF) prior to the study.
• Aged 18-75 years, male or female.
• Patients with histologically or cytologically confirmed non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC):The pathological type of NSCLC must be adenocarcinoma.For advanced NSCLC patients with positive EGFR sensitive mutations, ALK fusion, ROS1 fusion, RET fusion, BRAF V600E, or NTRK fusion mutations, they must have experienced disease progression after adequate targeted therapy for the corresponding mutation AND after at least one platinum-based chemotherapy regimen, or be intolerant to platinum-based therapy.Patients with NSCLC without driver gene mutations and patients with SCLC must have experienced disease progression after platinum-based chemotherapy with or without PD-1/PD-L1 inhibitors, or be intolerant to the aforementioned therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score: 0-2.
• At least one measurable lesion in the central nervous system (CNS).
• Patients who have not received chemotherapy, radiotherapy, surgical treatment, targeted therapy, or immunotherapy within 4 weeks prior to enrollment.
• All toxicities related to prior anti-tumor treatment must have recovered to ≤ Grade 1 (CTCAE v5.0), except for alopecia of any grade, which is permitted.
• CNS patients, based on screening brain Magnetic Resonance Imaging (MRI), must meet one of the following conditions:Untreated brain metastases not requiring immediate local therapy；Previously treated brain metastases, assessed by the investigator as having progressed after prior local CNS therapy and without clinical manifestations requiring immediate local therapy.
• Routine blood tests within 1 week prior to enrollment are essentially normal (based on the normal ranges of each research center's laboratory):

White blood cell count (WBC) ≥ 3.0 × 10\^9/L；

Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L；

Platelet count (PLT) ≥ 100 × 10\^9/L；

Hemoglobin ≥ 9.0 g/dL (Patients may receive blood transfusion or erythropoietin treatment to meet this criterion.)；

-Liver and kidney function tests within 1 week prior to enrollment are essentially normal (based on the normal ranges of each research center's laboratory):

Total bilirubin (TBIL) ≤ 1.5 × Upper Limit of Normal (ULN)；

Alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases)；

Aspartate aminotransferase (AST/SGOT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases)；

Creatinine clearance (Ccr) ≥ 60 ml/min；

• Expected survival ≥ 12 weeks.
• Men of reproductive potential and women of childbearing potential must agree to use reliable contraception from signing the ICF until 180 days after the last dose of study drug. Women of childbearing potential must have a negative serum pregnancy test result within ≤7 days before the first dose of study drug.

Exclusion Criteria for Lung Cancer with Brain Metastases:

• History of other malignancies (including primary brain or leptomeningeal tumors) within the past 5 years, except for cured basal cell skin carcinoma or cervical carcinoma in situ.
• Prior use of Utidelone injection or Bevacizumab.
• Imaging shows tumor invasion of major blood vessels, unclear demarcation from vessels, or judged by the investigator as having a high probability of fatal massive hemorrhage due to tumor invasion of important vessels during the study (major thoracic vessels include the thoracic aorta, left pulmonary artery, right pulmonary artery, 4 pulmonary veins, superior vena cava, inferior vena cava, and aorta).
• Major organ surgery (excluding needle biopsy) or significant trauma within 4 weeks prior to the first dose of study drug, or scheduled elective surgery during the trial period.
• History of Grade 3 or higher severe neurological adverse reactions related to prior anti-microtubule drug use.
• Any untreated brain lesion > 2.0 cm, unless discussed and approved for enrollment by the investigator.
• Ongoing use of systemic corticosteroids to control brain metastasis symptoms, with a total daily dose > 2 mg dexamethasone (or equivalent). However, a chronic stable dose ≤ 2 mg dexamethasone daily (or equivalent) may be permitted after discussion and approval by the investigator.
• Any brain lesion deemed to require immediate local treatment, including (but not limited to) lesions where increased size in an anatomical location or possible treatment-related edema may pose a risk to the patient (e.g., brainstem lesions). Patients receiving local treatment remain eligible for the study based on criteria described in the CNS inclusion criteria, as determined by screening contrast brain MRI.
• More than 2 episodes of seizures within 4 weeks prior to enrollment.
• Poorly controlled hypertension, or history of hypertensive crisis or hypertensive encephalopathy.
• History of hemoptysis within 6 months prior to enrollment, or evidence of bleeding tendency or significant coagulation dysfunction within the past month.
• Current use of full-dose warfarin or equivalent agents, or use of aspirin (325 mg/day) within 10 days.
• Major surgery, open biopsy, or significant traumatic injury within 28 days, or anticipated need for such during the study.
• Severe gastrointestinal toxicity prior to the first dose of study drug that has not recovered to below Grade 2; or confirmed presence of other clinically uncontrolled acute or chronic gastrointestinal diseases.
• History or presence of interstitial lung disease, emphysema, chronic obstructive pulmonary disease, pulmonary interstitial fibrosis, drug-induced interstitial lung disease, or radiation pneumonitis; or uncontrolled respiratory symptoms prior to the first dose of study drug.
• Clinically significant cardiovascular disease, including but not limited to:

Heart failure, myocardial ischemia or infarction, unstable angina, arrhythmia within the past 6 months or currently present, and New York Heart Association (NYHA) Class III-IV cardiac function.

Baseline ECG showing prolonged QT/QTc interval (QTcF: >450 ms for males, >470 ms for females).

Baseline echocardiogram (ECHO) showing left ventricular ejection fraction (LVEF) ≤ 50%.

Poorly controlled hypertension despite medication (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg).

History of cardiac surgery such as angioplasty, coronary artery bypass graft.

• Peripheral neuropathy ≥ Grade 2, or skin abnormalities such as rash ≥ Grade 2 requiring treatment prior to the first dose of study drug, or any toxicity from prior anti-tumor treatment that has not recovered to ≤ Grade 1 per CTCAE v5.0 (except for Grade 2 alopecia).
• History of drug abuse of psychotropic substances and inability to abstain, or patients with psychiatric disorders.
• Pregnant or breastfeeding women.
• Presence of any other non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that may interfere with treatment or follow-up.
• Known or suspected allergy to any study drug or excipient.
• Any reason that precludes the performance of brain magnetic resonance imaging with contrast.
• Any other condition deemed by the investigator to make the patient unsuitable for participation in this trial.
• Other conditions contraindicating the use of corticosteroids.