All Trans Retinoic Acid Combined with Toripalimab+Chemotherapy for Locally Advanced Inoperable or Metastatic Triple Negative Breast Cancer：a Multi-center, Multi-cohort Phase II Trial

Inclusion criteria

• The subjects voluntarily participate and sign a written informed consent form;
• Age ≥ 18 years old;
• For locally advanced inoperable or metastatic breast cancer confirmed by histology (according to AJCC 8th edition staging), the histology and pathology clearly showed that ER, PR, Her-2 were negative. If there was metastatic lesion pathology, the metastatic lesion histology and pathology should prevail. The definition of ER and PR negativity is: IHC ER<1%, IHC PR<1%. Her-2 negativity is defined as: immunohistochemical detection of Her-2 (-) or (1+), Her-2 (2+) must undergo FISH testing and the result is negative, Her-2 (-) or (1+) can choose to undergo FISH testing and the result is negative;
• According to RECIST 1.1 criteria for solid tumor evaluation, there must be at least one measurable lesion;
• Cohort 1: For locally advanced non operable or metastatic TNBC that has not been previously treated, intravenous chemotherapy and anti-tumor therapy may be used during previous neoadjuvant and/or adjuvant therapy stages, provided that the interval between the end of neoadjuvant and/or adjuvant therapy and the occurrence of recurrence/metastasis is ≥ 12 months; Cohort 2: Local late stage inoperable or metastatic TNBC with previous treatment failures of at least one line or above;
• All subjects should undergo tumor lesion biopsy during the screening period to obtain sufficient qualified tumor tissue specimens for retrospective biomarker analysis (including PD-L1 expression levels) in their cohort. If subjects are unable to undergo biopsy, they should provide tumor samples or unstained sections (3-5 μm) that have been fixed in formalin and embedded in paraffin (FFPE) closest to the start of the study treatment (up to 24 months) for corresponding biomarker analysis;
• The main organ function is good, the relevant examination indicators within 14 days before treatment meet the following requirements:

Without blood transfusion, platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 90g/L, neutrophil count (ANC) ≥ 1.5 × 10^9/L AST and ALT ≤ 2.5 x upper limit of normal (ULN), ≤ 5 x ULN if liver metastasis is present, total bilirubin ≤ 1.5 x ULN, serum creatinine (Cr) ≤ 1.5 ULN, or creatinine clearance rate ≥ 60mL/min (Cockcroft Gault formula)

• Expected survival period ≥ 3 months;
• ECOG PS score: 0-1 points;
• Non surgical sterilization, male patients with women of childbearing age or partners of childbearing age, are required to use a medically approved contraceptive measure (such as intrauterine device, contraceptive pill, or condom) during the study treatment period and within 6 months after the end of the study treatment period; Female patients of childbearing age who undergo non-surgical sterilization must have a negative serum HCG test within 72 hours prior to enrollment in the study.

Exclusion criteria

• Individuals who have previously been treated with PD-1 or PD-L1 monoclonal antibodies; Participants in cohort 1 who have previously used albumin paclitaxel;
• Individuals known to be allergic to any of the drugs in the study;
• Patients who have hypersensitivity reactions to other vitamin A drugs;
• History of active autoimmune diseases requiring systemic treatment in the past 2 years (e.g. corticosteroids (dose ≤ 10mg/day, except for prednisone or other effective hormones) or immunosuppressive drugs);
• Diagnosed with immune deficiency or undergoing systemic steroid therapy (excluding doses ≤ 10mg/day of prednisone or other effective hormones) or any other form of immunosuppressive therapy within 7 days prior to enrollment;
• There are other known malignant tumors that have progressed or require active treatment in the past 5 years. Excluding malignant tumors that can be treated locally and have already been cured, such as skin basal cell carcinoma, skin squamous cell carcinoma, and cervical cancer in situ;
• Known to have active central nervous system (CNS) metastases;
• History of non infectious pneumonia requiring steroid hormone therapy;
• Active infections require systematic treatment;
• There are serious uncontrolled hypertension, diabetes and hyperlipidemia;
• History of II-IV congestive heart failure or myocardial infarction within 6 months prior to enrollment;
• Individuals who tested positive for HIV during screening;
• Active hepatitis (hepatitis B reference: HBsAg positive and HBV DNA ≥ 500 IU/ml; hepatitis C reference: HCV antibody positive and HCV copy number>upper limit of normal value);
• Individuals with other serious acute or chronic physiological or mental problems;
• Accepting any medication that is prohibited from being used in combination with the investigational drug, unless the medication has been discontinued within 7 days prior to enrollment;
• Lactating women;
• Individuals who have participated in clinical trials of other anti-tumor drugs within the past four weeks;
• Inability to swallow, intestinal obstruction, or other factors that affect medication administration and absorption;
• Any situation that other researchers consider unsuitable for participation in this study.