Metronomic Oral Paclitaxel Monotherapy and Combined Immunotherapy for Advanced HER2-Negative Breast Cancer: A Two-Stage Dose Exploration and Expansion Trial

Inclusion criteria

1.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.

3.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.

4.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.

12.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.

Exclusion criteria

• Patients with suspected major infectious diseases, neurological disorders, or intestinal obstruction.
• Patients with a diagnosis of other cancer types (except non-melanoma skin cancer, cervical carcinoma in situ, or other cancers with no recurrence or metastasis for ≥5 years and considered cured).
• Patients who have undergone major surgery, including organ resection within 4 weeks before enrollment, or radiotherapy within 2 weeks before enrollment.
• Disease progression during prior taxane salvage therapy (at least 2 cycles completed), or recurrence/metastasis within 12 months after neoadjuvant/adjuvant therapy.
• Patients requiring long-term concomitant use of P-glycoprotein (P-gp) inhibitors or immunosuppressive agents during the study.
• Patients receiving long-term treatment with steroids or other immunosuppressive agents (except oral, topical, or local injection).
• Patients with myocardial infarction, congestive heart failure, rapidly changing arrhythmia on ECG, severe or unstable angina pectoris, or other serious heart diseases.
• Patients with other severe medical diseases (uncontrolled diabetes mellitus and hypertension, chronic obstructive pulmonary disease (COPD), or dyspnea at rest due to any cause).
• Patients with a history of drug or alcohol abuse within the past 3 months.
• Pregnant or breastfeeding women, or patients who cannot or will not use effective contraceptive methods.
• Patients with or suspected of having bile acid excretion disorders.
• Active tendency of gastrointestinal bleeding or use of oral vitamin K antagonists (low-dose warfarin and acetylsalicylic acid are allowed as long as INR ≤2.0).
• Patients with severe hypersensitivity to the active ingredients or excipients of the study drugs.
• History of HIV seropositivity (HIV testing is not mandatory).
• Gastrointestinal dysfunction or diseases that may significantly alter the absorption of study drugs (e.g., ulcerative diseases, poorly controlled nausea, vomiting, diarrhea, malabsorption syndrome), except patients with prior gastrectomy.
• Patients receiving enteral feeding (e.g., via nasogastric tube, nasointestinal tube, gastrostomy, or jejunostomy).
• Patients with visceral crisis, or patients with excessive tumor burden, rapid disease progression who urgently require rapid tumor shrinkage (e.g., conventional maximum tolerated dose chemotherapy) to relieve severe clinical symptoms per investigator assessment.
• Patients considered inappropriate for the clinical trial by the investigator.