A Study of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2

Inclusion Criteria:

• Voluntarily agree to participate in the study and sign the informed consent;
• Subjects aged 18-70 years (including 18 years and 70 years) and not reaching the 71stbirthday were all considered to be ≤70 years old;
• Expected survival ≥12 weeks;
• Eastern Cooperative Oncology Group(ECOG) physical condition 0 or 1;
• For female subjects of child-bearing age women agreed to study during treatment andexperimental subjects within 6 months after the end of the treatment period using anapproved by the medical contraception (e.g. intrauterine device, the pill or condoms),before the study drug delivery within 7 days of pregnancy blood test must be negative (sterilization surgery or age 60 or more subjects can choose no pregnancy blood test),and must be an lactation. For male subjects: should be sterilized surgically, or agreeto use a medically approved contraceptive method during the study period and for 6months after the end of the treatment period. Control subjects after the end of thetreatment period according to the choice of control drugs to determine the length ofcontraception.
• Able to understand the study requirements and be willing and able to follow the studyand follow-up procedures.
• Bone marrow function: hemoglobin ≥9g/dL; absolute neutrophil count ≥1.5×109/L; white blood cell count ≥3.0×109/Lplatelet ≥100 ×109/L;
• Liver function (according to the normal value of the clinical trial center) : serum total bilirubin ≤1.5 times the upper limit of normal value (ULN); alanineaminotransferase (ALT), aspartate aminotransferase(AST) and Alkaline phosphatase（ALP） were ≤2.5 × ULN in the absence of liver metastasis, and ALT, AST and Alkaline phosphatase(ALP)were ≤5 × ULN in the presence of liver metastasis
• Renal function (according to the normal value of the clinical trial center) : serum creatinine ≤1.5×ULN, or calculated by Cockcroft-Gault formula, the creatinineclearance rate (CrCl) ≥60 mL/min;
• Cardiac function: American New York college of cardiology (NYHA) grade < 3; left ventricular ejectionfraction ≥50%;
• Breast cancer subjects diagnosed by histology and / or cytology are currently at alocally advanced or metastatic stage and cannot be radically removed;
• The low expression of HER2 confirmed by the IHC and FISH results of the centrallaboratory (defined as: IHC 2+ and no amplification of FISH); the subject can providea specimen of the primary or metastatic tumor site (paraffin wax) for HER2 detectionBlock, paraffin-embedded section or fresh tissue section can be used);
• Previous use of anthracycline drugs;
• Received 1 or 2 systemic chemotherapy treatments after relapse / metastasis. Subjectswho relapsed during adjuvant chemotherapy or within 12 months after the end ofadjuvant chemotherapy were considered to have failed first-line chemotherapy afterrelapse / metastasis.
• Hormone receptors are negative or positive. Hormone receptor-positive subjects need toprogress after receiving endocrine therapy after relapse / metastasis or relapse afterless than 2 years. Patients who are not suitable for endocrine therapy can be includedin this study after undergoing chemotherapy treatment (first-line or second-line);
• The imaging evidence confirmed by the investigator that the tumor disease progressedduring or after the most recent treatment is required;
• There has been no diagnosis of HER2 positive (HER2 IHC 3+ or FISH amplification)
• Have not used drugs targeting HER2 (including antibodies, small molecule Tyrosinekinase inhibitor（TKIs） and antibody drug conjugates).
• According to the RECIST 1.1 standard, there is at least one measurable lesion.

Exclusion Criteria:

• Received chemotherapy within 4 weeks before the start of study administration (treatment with nitrosourea and mitomycin C within 6 weeks, oral fluorouracil within 2weeks), radiotherapy (palliative for bone metastases Local radiotherapy is within 2weeks before study administration), immunotherapy; received endocrine therapy forbreast cancer within 2 weeks before study administration;
• The research drug was used within 4 weeks before the start of study administration;
• Have undergone major surgery within 4 weeks before the start of study administration;
• Have received a live vaccine within 4 weeks before the start of study administrationor plan to receive any vaccine during the study period;
• Serious cardiovascular and cerebrovascular events occurred within 12 months, includingbut not limited to unstable angina, myocardial infarction, cerebral hemorrhage, andcerebral infarction (except for asymptomatic and untreated lacunar infarction)；
• Those who are suffering from heart disease are not suitable for enrollment, includingbut not limited to arrhythmia and heart failure requiring medical treatment oraccompanied by symptoms;
• There are other lung diseases requiring treatment or serious, including but notlimited to active pulmonary tuberculosis, interstitial lung disease, etc ;
• Suffering from active infection requiring systemic treatment;
• Have active autoimmune diseases (such as the use of corticosteroids orimmunosuppressive drugs, etc.) that require systemic treatment within the past 2years, allowing related alternative treatments (such as thyroxine, insulin, or thephysiology of adrenal or pituitary insufficiency Corticosteroid replacement therapy);
• The toxicity of the previous anti-tumor therapy has not been restored to the 0 to 1level defined by CTCAE version 5.0, of which the neurotoxicity has not been restoredto 0; except for hair loss, pigmentation or other researches that do not increase therisk of medication Happening;
• Have a clear past or current history of neurological or mental disorders, includingepilepsy or dementia;
• According to the investigator's judgment, there are concomitant diseases thatseriously endanger the safety of the subject or affect the completion of the clinicalstudy；
• Positive HIV test results; patients with active hepatitis B or C (HBsAg positive andhepatitis B virus（HBV） DNA titers above the upper limit of normal; Hepatitis C VirusAntibody(HCVAb) positive hepatitis C virus （HCV） RNA titers above the upper limit ofnormal)；
• There is a third interstitial fluid that cannot be controlled by drainage or othermethods (including a large amount of pleural effusion or ascites);
• Known hypersensitivity or delayed allergic reaction to certain components of RC48-ADCor similar drugs;
• Subjects who are not suitable for using any of the alternative control drugs;
• The presence of brain metastases and / or cancerous meningitis;
• Have other malignant tumors within 5 years before signing the informed consent form (except for non-melanoma skin cancer, cervical carcinoma in situ or other tumors thathave been effectively treated, except malignant tumors that are considered cured);
• Subjects who are estimated to be inadequate for patients to participate in thisclinical study or other factors that the investigator believes are inappropriate toparticipate in this study;