Metronomic Oral Paclitaxel Monotherapy for Advanced HER2-Negative Breast Cancer: A Two-Stage Dose-Finding and Expansion Study
The goal of this clinical trial is to evaluate the safety, tolerability, and preliminary anti-tumor activity of metronomic oral paclitaxel solution in patients with advanced HER2-negative breast cancer who have previously received systemic anti-cancer treatments. The main questions this study aims to answer are: What doses of metronomic oral paclitaxel solution can be safely administered to patients with advanced HER2-negative breast cancer? How well does metronomic oral paclitaxel solution control tumor growth? What side effects and treatment-related medical problems occur during treatment? This study will include two stages. In the first stage, researchers will evaluate different dosing schedules of oral paclitaxel solution to identify a dose（OTD） with an acceptable balance between safety and potential anti-tumor activity. In the second stage, additional participants will receive the selected dose（OTD） to further evaluate its effectiveness and safety. Participants will: Receive metronomic oral paclitaxel solution according to the assigned dose schedule. Visit the study clinic regularly for physical examinations, laboratory tests, tumor imaging assessments, and safety evaluations. Complete assessments of treatment response, side effects, and quality of life during the study. Continue follow-up after treatment to collect information about disease status and survival.
• Age ≥ 18 years, male or female. 2.Histologically confirmed unresectable locally advanced, recurrent, or metastatic HER2-negative breast cancer, regardless of hormone receptor (HR) status. For patients with HR+/HER2-negative subtype: prior treatment with at least 1 line of CDK4/6 inhibitor plus endocrine therapy is required, and the patient is considered no longer suitable for further endocrine therapy by the investigator.
• Patients have received 1-4 prior lines of systemic anti-tumor therapy for recurrent or metastatic disease.
⁃ Line of therapy is defined as a systemic treatment regimen for recurrent or metastatic disease. First-line therapy is the first regimen used in the recurrent/metastatic setting; any subsequent regimen that adds a new drug class (e.g., anti-angiogenic, immunotherapy) is considered a new line.
⁃ Neoadjuvant or adjuvant therapy is not counted as a treatment line.
⁃ Disease recurrence \>6 months after neoadjuvant therapy is counted as first-line; recurrence ≤6 months is considered continuation of prior therapy and not a new line.
⁃ Disease recurrence \>12 months after adjuvant therapy is counted as first-line; recurrence ≤12 months is considered continuation of prior therapy, and subsequent regimens start at second-line.
• Prior treatment with taxane is allowed if both criteria are met:
⁃ Interval from last dose of taxane to first study dose ≥ 4 weeks;
⁃ No unresolved taxane-related Grade ≥3 toxicity in the past. 5.Body surface area (BSA): 1.38 m² ≤ BSA ≤ 1.87 m². 6.ECOG performance status 0-1. 7.At least one measurable lesion per RECIST 1.1. 8.Expected survival ≥ 12 weeks. 9.Adequate bone marrow function: ANC ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 90 g/L 10.Adequate hepatic function: Total bilirubin ≤ 1.5 × ULN ALT/AST ≤ 2.5 × ULN (no liver metastasis) ALT/AST ≤ 5 × ULN (with liver metastasis) 11.Adequate renal function: Serum creatinine ≤ 1.5 mg/dL Or creatinine clearance (Ccr) ≥ 60 mL/min (calculated by Cockcroft-Gault formula) if serum creatinine \>1.5 mg/dL.
⁃ Pre-existing peripheral neuropathy \< Grade 2 (CTCAE v6.0). 13.Known CNS metastases are allowed only if all of the following are met:
⁃ CNS lesions stable for ≥4 weeks before enrollment, per RANO-BM criteria (no new lesions, target lesion volume change \<20%, no clear progression of non-target lesions on baseline and follow-up MRI).
⁃ No corticosteroid use, or current dexamethasone ≤4 mg/day (or equivalent), with no dose increase within 7 days before enrollment.
⁃ For patients with prior local CNS treatment: no imaging progression after treatment completion; neurologic symptoms stable for ≥2 weeks before first study dose; no steroid or ≤4 mg/day dexamethasone (or equivalent).
⁃ No leptomeningeal disease.
⁃ Whole-brain radiotherapy completed \>14 days before enrollment.
⁃ Prior stereotactic radiosurgery is allowed.
⁃ Prior CNS surgery completed \>28 days before enrollment with full recovery. 14.Voluntary participation and signed written informed consent.