Tucidinostat and Metronomic Capecitabine for Metastatic Triple-negative Breast Cancer:a Multicenter,Open-label, Randomized Controlled, Phase II Clinical Trial

Tucidinostat and Metronomic Capecitabine for Metastatic Triple-negative Breast Cancer:a Multicenter,Open-label, Randomized Controlled, Phase II Clinical Trial

The objective of this study is to explore and evaluate the efficacy of tucidinostat combined with metronomic capecitabine in the treatment of metastatic triple-negative breast cancer.

Inclusion Criteria:

1. ≥18 years old, female; 2. Histologically confirmed triple-negative metastatic breast cancer [HER2 negative is defined as immunohistochemistry(IHC) 0 or IHC 1+, and if the score of IHC is 2+, fluorescence in situ hybridization technology (FISH) test must be negative, subjects with ER ≤ 10% and PR ≤ 10% and those with no benefit from endocrine therapy in the investigator's judgment are allowed to enroll]; 3. Metastatic breast cancer that has failed at first-line taxane therapy; definition of taxane treatment failure: disease progression during rescue therapy, or recurrence and metastasis within 12 months after completion of adjuvant therapy; 4. ECOG score 0-1; 5. According to RECIST1.1 criteria, at least there is one measurable lesion； 6. The main organ and bone marrow function levels meet the following requirements:

1. Blood routine: neutrophil (ANC) ≥ 1.5×109/L; platelet count (PLT) ≥ 90× 109/L; hemoglobin (Hb) ≥ 90g/L; It is required that no blood products (including red blood cells and platelet products, etc.) have been transfused and no growth factors (including colony-stimulating factor, interleukin, and erythropoietin, etc.) have been used for supportive treatment within 2 weeks before the examination.
2. Liver function: serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (with liver Requirements for metastatic patients: ALT and AST≤5×ULN);
3. Renal function: serum creatinine (Cr)≤1.5×ULN or creatinine clearance rate>60mL/min; 7. Expected survival time ≥ 3 months; 8. Voluntary participation study, signed written informed consent.

Exclusion Criteria:

1. Known hypersensitivity to capecitabine or tucidinostat; patients with previous severe, unexpected reactions to fluoropyrimidines or known hypersensitivity to fluoropyrimidines;
2. Patients with complete deficiency of dihydropyrimidine dehydrogenase (DPD) activity;
3. Received palliative radiotherapy for target lesion within 4 weeks before enrollment;
4. Previously received treatment with histone deacetylase inhibitors，or have previously received fluoropicidine drugs such as capecitabine and stopped drugs due to progress (if it is used in the adjuvant phase, then the progress of the treatment within 1 year after the suspension of the drug was stopped, and the group cannot be admitted to the study).
5. Patients with gastrointestinal perforation, fistula, abdominal abscess, gastrointestinal ulcer or active diverticulosis before enrollment;
6. Significant malnutrition (weight loss > 5% in the past 1 month or > 15% in the past 3 months, or food intake decreased by 1/2 or more in the past week), or still need to rely on intravenous nutritional support during the screening period;
7. Toxicities that did not recover to National Cancer Institute Common Adverse Event Terminology Version 5.0 (NCICTCAEv5.0) grade 0 or 1 toxicity from prior antineoplastic therapy prior to the first dose of study treatment(alopecia, grade 2 fatigue, grade 2 anemia, non-clinically critical and asymptomatic laboratory abnormalities can be enrolled);
8. Patients with currently symptomatic brain or meningeal metastasis;
9. Received immunosuppressive drugs within 4 weeks before enrollment, excluding nasal spray, inhalation or other local glucocorticoids or physiological doses systemic glucocorticoids (no more than 10 mg/day of prednisone or other glucocorticoids at an equivalent dose), or use of glucocorticoids for the prevention of contrast medium allergy;
10. The patient has any active autoimmune disease or has history of immune disorders (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism, hypothyroidism; patients with vitiligo or complete remission of asthma in childhood without any intervention in adulthood can be included; those with asthma that require medical intervention with bronchodilators are not included);
11. Patients with active pulmonary tuberculosis who are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening;
12. Complications requiring long-term use of immunosuppressive drugs, or systemic or topical use of corticosteroids with immunosuppressive doses;
13. Received any anti-infection vaccine (such as influenza vaccine, chickenpox vaccine, etc.) within 4 weeks before enrollment;
14. Received major surgery (craniotomy, thoracotomy or laparotomy) within 4 weeks before enrollment or is expected to undergo major surgery during the study treatment period; received exploratory laparoscopic surgery within 2 weeks prior to enrollment;received central venous catheterization within 7 days prior to enrollment;
15. Concurrent participation in another interventional clinical study, unless participating in an observational (non-interventional) clinical study or in the safety follow-up of an interventional study Stage;
16. Known acute or chronic active hepatitis B (HBsAg positive and HBV DNA virus Load ≥ULN or ≥10^3 copies/mL) or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA positive);
17. Severe heart disease or discomfort, including but not limited to the following diseases: 1) Diagnosed history of heart failure or systolic dysfunction (LVEF<50%); 2) arrhythmias requiring medical treatment or clinically significant; 3) high-risk uncontrolled arrhythmias, such as atrial tachycardia, resting heart rate > 100 bpm, significant ventricular arrhythmia (such as ventricular tachycardia) or higher-grade AV block (ie Mobitz II second-degree AV block or third-degree AV block); 4) Angina pectoris; 5 ) Clinically significant valvular heart disease; 6) ECG shows transmural myocardial infarction; 7) Any other heart disease judged by the investigator to be inappropriate to participate in this trial, etc.;
18. Inability to swallow, bowel obstruction, or other factors that interfere with drug taking and absorption;
19. A history of immunodeficiency, including HIV test positive, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation;
20. Pregnant, lactating female patients, female patients of childbearing potential with a positive baseline pregnancy test, or patients of childbearing age who are unwilling to use effective contraception throughout the trial and within 6 months after the last study drug;
21. Serious concomitant disease or other comorbidities that would interfere with planned treatment;
22. Any other conditions deemed inappropriate by the investigator to participate in this study.