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

A Single-Arm, Open-Label, Phase II Clinical Study of Utidelone and Bevacizumab With or Without Etoposide in Patients With Brain Metastases From Malignant Solid Tumors

Brain metastasis represents one of the worst prognostic outcomes in advanced malignant tumors. Approximately 10% to 40% of patients with solid tumors develop brain metastases, a incidence rate significantly higher than that of primary malignant brain tumors. Over 80% of patients present with multiple brain metastases at diagnosis, often precluding surgical intervention.

Brain metastases typically occur in the late stages of cancer. Patients have often received multiple prior therapies and developed resistance to first- and second-line drugs, leaving limited pharmacological options. The rapid growth of intracranial tumors poses an immediate threat to life. Consequently, radiotherapy and surgery currently form the cornerstone of clinical management for these patients. Thus, developing effective systemic therapies is an urgent and unmet medical need .

Utidelone, a new-generation epothilone anticancer agent, has demonstrated good efficacy and safety. Previous studies indicate that utidelone achieves higher concentrations in most tissues, including the brain, compared to plasma, suggesting its ability to readily cross the blood-brain barrier . Furthermore, a Phase III clinical trial in metastatic breast cancer showed that utidelone in combination with capecitabine significantly improved the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared to capecitabine alone in patients previously treated with anthracyclines and taxanes .

A separate Phase II study demonstrated that bevacizumab combined with carboplatin achieved a central nervous system objective response rate (CNS ORR) of 63%, with a median PFS of 5.62 months and a median OS of 14.1 months in breast cancer patients with brain metastases . Regarding safety, utidelone has a relatively low incidence of adverse reactions aside from peripheral neurotoxicity .

Based on this evidence, this proposed study aims to evaluate the efficacy and safety of utidelone and bevacizumab, combined with etoposide for breast cancer cohorts or without etoposide for lung cancer cohorts, in patients with malignant tumor brain metastases.

Brain metastases from malignant tumors often occur in the advanced stages of the disease. Patients have typically undergone multiple treatments and developed resistance to first- and second-line drugs, leaving limited therapeutic options. Furthermore, the rapid growth of intracranial tumors is life-threatening. Therefore, the current mainstay of clinical treatment for patients with malignant brain metastases is radiotherapy and surgery. There is a significant unmet clinical need for systemic treatment options that offer short-term benefits and a low risk of inducing drug resistance. Utidelone, as a new-generation microtubule inhibitor, is not a substrate for P-glycoprotein, which contributes to its low potential for inducing resistance. Its small molecular size enables it to cross the blood-brain barrier. In clinical practice, it has shown good efficacy in patients with brain metastases. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) receptor. It exerts its effect by binding to VEGF, thereby blocking downstream signaling pathways, effectively inhibiting tumor growth with high specificity [8]. Studies have shown that administering Bevacizumab to glioma patients undergoing radiotherapy and chemotherapy can effectively improve immune function, enhance therapeutic efficacy, and prolong survival .

A phase II clinical study led by Professor Shi Yehui from Tianjin Cancer Hospital explored the efficacy of a regimen combining Utidelone, Etoposide, and Bevacizumab in patients with HER2-negative breast cancer and brain metastases. Key data from this study were selected for poster presentation at ESMO 2023 and later for a Rapid Oral Abstract presentation at ASCO 2025, receiving recognition at international academic conferences. This confirms that the Utidelone-based combination regimen provides significant survival benefits for this patient population. Patient enrollment for this study has been completed, with some patients still under follow-up. Building on the breakthrough in treating breast cancer brain metastases, this research will further explore the clinical value of Utidelone-based combination regimens in patients with lung cancer brain metastases. Regarding other malignant tumors: Research directions and treatment plans for other cancer types will be determined after the completion of the breast and lung cancer studies and the assessment of their efficacy and safety.

This study is a single-arm, multicenter, open-label, phase II clinical trial recruiting patients with lung cancer brain metastases. Eligible patients will receive treatment with a regimen combining Utidelone and Bevacizumab.

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.