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

Overview

The goal of this clinical trial is to learn if oral paclitaxel solution (metronomic scheduling) works to treat advanced HER2-negative breast cancer in adults. It will also learn about the safety of oral paclitaxel solution alone and combined with toripalimab. The main questions it aims to answer are: What is the optimal tolerated dose (OTD) of metronomic oral paclitaxel solution? Does metronomic oral paclitaxel plus toripalimab improve progression-free survival (PFS)? What medical problems do participants have when taking the study treatments? Researchers will evaluate metronomic oral paclitaxel alone (dose-finding) and metronomic oral paclitaxel plus toripalimab (expansion cohort) to see if the regimens work to treat advanced HER2-negative breast cancer. Participants will: Receive metronomic oral paclitaxel solution (one of two dose levels) once daily or three times weekly After OTD is determined, receive metronomic oral paclitaxel plus toripalimab every 3 weeks Visit the clinic regularly for safety checks, blood tests, and tumor imaging Keep records of treatment compliance and health-related quality of life

Interventions

• Drug Paclitaxel Oral Solution
  Paclitaxel oral solution, 50 mg orally once daily (QD), continuously administered. Each treatment cycle is 21 days.
• Drug Paclitaxel Oral Solution
  Paclitaxel oral solution, 100 mg orally three times weekly (TIW). Each treatment cycle is 21 days.
• Drug Toripalimab
  Optimal tolerated dose (OTD) of metronomic paclitaxel oral solution plus toripalimab 240 mg intravenously on day 1 of each 21-day cycle.

Primary outcome measures

• Optimal Tolerated Dose (OTD) of metronomic oral paclitaxel [Time frame: TRAE assessment: Within 7 days after the first dose DCR assessment: At the first efficacy evaluation (planned at 6 weeks after the first dose)]
• Progression-Free Survival (PFS) [Time frame: Up to approximately 24 months from the first dose of combination therapy]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Mo H, Yu Y, Sun X, Ge H, Yu L, Guan X, Zhai J, Zhu A, Wei Y, Wang J, Yan X, Qian H, Xu B, Ma F. Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial. Nat Med. 2024 Sep;30(9):2528-2539. doi: 10.1038/s41591-024-03088-2. Epub 2024 Jul 5. PMID 38969879

Identifiers

NCT: NCT07602907 · METRO-IO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗