A Pivotal Phase II Clinical Trial of Utidelone Injection Plus Capecitabine in HER2-negative Breast Cancer Patients with Brain Metastases

This study is a multicenter, two-stage clinical trial to evaluate the efficacy and safety of utidelone in combination with capecitabine in patients with HER2-negative breast cancer with brain metastases. Patients will be enrolled to receive treatment of utidelone alone or in combination with capecitabine.

The objectives both in stage I and stage II are to evaluate the intracranial and systemic efficacy and safety of utdelone plus capecitabine for the treatment of HER2-negative breast cancer patients with brain metastases.


Eligibility Criteria:
Inclusion Criteria:

1. Have histologically confirmed HER2-negative metastatic breast cancer. HER2-negative defined as immunohistochemical (IHC) score of 0 or 1+, or IHC2+ with negative HER2 expression on in situ hybridization (ISH). (According to the 2023 American Society of Clinical Oncology \[ASCO\]/ College of American Pathologists \[CAP\] guidelines).
2. Based on screening contrast-enhanced brain MRI, patients must have at least one measurable intracranial lesion according to RECIST 1.1 (≥1.0 cm in size) and must have one of the following: A) Untreated brain metastases not needing immediate local therapy. B) Brain metastases progressing after prior local therapy.
3. Male or female aged ≥18 years.
4. ECOG PS 0 or 1.
5. Have a life expectancy of at least 3 months.
6. Have adequate baseline hematologic parameters.
7. Have adequate hepatic and renal function.
8. ≤ 3 prior lines of chemotherapy in advanced or metastatic setting.
9. Women of childbearing potential, unless hysterectomy or oophorectomy or postmenopausal for at least 12 consecutive months, must use an effective method of avoiding pregnancy (including oral, transdermal, or implanted contraceptives \[any hormonal method in conjunction with a secondary method\], intrauterine device, female condom with spermicide, diaphragm with spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or sterile \[at least 6 months prior to study drug administration\] sexual partner) for at least 4 weeks prior to study drug administration, during study and up to 6 months following the last dose of study drug. Cessation of birth control after this point should be discussed with a responsible physician. Investigator will discuss with patient on the above points and the patient agreement will be documented in the source document. The investigator should ensure that the patient is using an effective method of avoiding pregnancy as per protocol. In case of Male patients: Either patient partners or patients themselves must use an effective method of avoiding pregnancy for at least 4 weeks prior to study drug administration, during study and up to 6 months following the last dose.
10. Patients must be able to follow the study visit schedule, and must be able of sign and give informed consent in accordance with institutional review board.

Exclusion Criteria:

1. Leptomeningeal metastasis confirmed by MRI and/or cerebrospinal fluid cytology.
2. Any intracranial lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions).
3. Have poorly controlled (\> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
4. Had evidence of intracranial hemorrhage within 12 months before study treatment.
5. Had evidence of hemoptysis within 6 months before study treatment. Or bleeding or evidence of coagulopathy within 4 weeks before study treatment.
6. Undergone major surgical procedures within 4 weeks or not fully recovered from surgery before study treatment.
7. Patients who have received anti-tumor therapies within 4 weeks (6 weeks for nitrosoureas or mitomycin) or 5 half-lives (≥ 2 weeks) before the first dose of investigational product, including chemotherapy, radiotherapy, biotherapy, targeted therapy, immunotherapy, antibody-drug conjugate therapy or traditional Chinese medicine treatment with anti-tumor indications.
8. Persistent toxicities caused by previous antitumor therapy (excluding alopecia), not yet improved to CTCAE v5.0 grade ≤ 1 or baseline.
9. Patients with neuropathy\> grade 1.
10. Known hypersensitivity to any components of the investigational product.
11. Known deficiency of dihydropyrimidine dehydrogenase (DPD).
12. Have no response to prior capecitabine therapy (no response was defined as best response is PD during capecitabine combination or monotherapy); or patients who had response to prior capecitabine therapy in advance setting but disease progression less than 6 months after discontinuation of capecitabine; or patients who had response to prior capecitabine (neo)adjuvant therapy but disease progression less than 12 months ago after discontinuation of capecitabine.
13. Patients who are pregnant (positive pregnancy test) or lactating.
14. Patients with other malignancies over the past 5 years, except for cured skin basal cell carcinoma, in-situ carcinoma of the cervix, or papillary thyroid cancer.
15. Patients also participate in another interventional study or receive other study treatments.
16. Known active or uncontrolled hepatitis B infection, active syphilis, or HIV infection that is not well controlled; or positive for hepatitis B virus based on the evaluation of results of tests for hepatitis B (HBsAg, anti-HBs, anti-HBc, or HBV DNA) infection at screening.
17. With a history of severe or uncontrolled diseases.
18. Autoimmune diseases requiring treatment with systemic glucocorticoids.
19. Not able to perform contrast-enhanced brain MRI or known contraindications to MRI gadolinium contrast, such as cardiac pacemaker, shrapnel, or eye foreign body.
20. Patients with a history of other systemic severe diseases or abnormal laboratory findings that would, in the Investigator's judgment, be inappropriate for this study.