Targeted combo therapy for HER2-expressing advanced solid tumors

Inclusion Criteria:

* The subjects voluntarily joined this study, signed an informed consent form, and had good compliance;
* Age between 18 and 75 years old (calculated based on the date of signing the informed consent form);
* Eastern Cooperative Oncology Group (ECOG) score from 0 to 1;
* Expected survival is greater than 12 weeks;
* Advanced solid tumors with HER2 expression confirmed by histopathological/cytological examination. HER2 expression includes HER2 positive (including Immunohistochemistry (IHC) 3+, IHC 2+and Fish positive), HER2 low expression (including IHC 1+ IHC 2+and Fish negative, HC 0 but with HER2 expression);
* Confirm the presence of at least one measurable lesion according to RECIST 1.1 criteria;
* The laboratory inspection meets the following standards:

  * Blood routine: Hemoglobin (HGB) levels in the past 14 days without the use of growth factors or blood transfusions

    * 90g/L ； Neutrophil absolute value (NEUT) ≥ 1.5 × 10 9/L; Platelet count (PLT)
    * 100×10 9 /L ；
  * Liver function: For patients without liver metastasis, total bilirubin (TBIL) is ≤ 1.5 times the upper limit of normal (ULN), For patients with liver metastasis, total bilirubin (TBIL) ≤ 3.0 times the upper limit of normal (ULN); Alanine group Transferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If accompanied by liver transformation Move, then ALT and AST ≤ 5 × ULN;
  * Renal function: Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance rate (CCr) ≥ 60 ml/min (Using the standard Cockcroft Gault formula);
  * Urine routine test shows a urine protein concentration of ≤ 1+; If urinary protein is ≥ 2+, it needs to be tested for 24 hours within 7 days Urine protein quantitative testing can only be selected when the 24-hour urine protein is less than 1g;
  * Coagulation function: Prothrombin time (PT), activated partial thromboplastin time (APTT) International Normalized Ratio (INR) ≤ 1.5 × ULN;
  * Cardiac function: Left ventricular ejection fraction ≥ 50%;
* Women of childbearing age should agree to use effective contraceptive measures during the study period and for 6 months after the end of the study Shi had a negative serum pregnancy test within 7 days prior to enrollment in the study; Men should agree during and after the study period Effective avoidance measures must be taken within 6 months after completion.

Exclusion Criteria:

* Patients with known spinal cord compression or active central nervous system metastasis (defined as untreated or symptomatic metastasis, or requiring corticosteroids or anticonvulsants to control related symptoms) are excluded, unless they have been stable for at least 4 weeks after treatment (no new or expanding imaging evidence of brain metastasis) and have not used corticosteroids and anticonvulsants within 2 weeks before randomization.
* Subjects with only cutaneous and/or intracranial lesions as target lesions.
* Concurrent diseases and medical history:

  * Have had or currently have other malignant tumors within 5 years, except for the following conditions: cured carcinoma in situ of the cervix, non-melanoma skin cancer, and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invades the basement membrane)\], differentiated thyroid cancer, and colorectal intra-mucosal cancer;
  * The adverse reactions from previous treatments have not recovered to a Common Terminology Criteria for Adverse Events Version (CTCAEv5.0) score of ≤1, except for Grade 2 alopecia, Grade 2 peripheral neurotoxicity, Grade 2 anemia, non-clinically significant and asymptomatic laboratory abnormalities, and stable hypothyroidism treated with hormone replacement therapy, which the investigator deems to pose
  * Those who have undergone major surgical treatment, significant traumatic injury, or are expected to undergo major surgery during the study treatment period (excluding surgeries specified in the protocol) within 4 weeks before the first dose, or have long-term unhealed wounds or fractures (excluding pathological fractures, but if there is severe bone damage in bone metastases and it may affect survival, it needs to be excluded). (Major surgery is defined as surgeries at or above level 3 in the National Surgical Classification Catalogue 2022 edition);
  * There are diseases that affect intravenous injection and venous blood sampling;
  * Subjects with congenital bleeding or coagulation dysfunction, or those who have experienced bleeding or coagulopathy within 28 days prior to the commencement of study treatment, or who have taken aspirin \>325 mg/day (the maximum antiplatelet dose) within 7 days prior to the commencement of study treatment;
  * Cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction, except for asymptomatic and non-treatment-required lacunar cerebral infarction) or pulmonary embolism occurred within 6 months before the first dose; currently, there is deep venous thrombosis requiring therapeutic intervention;
  * Poor blood pressure control (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg);
  * Suffering from major cardiovascular diseases, including any of the following conditions:

    * Cardiac insufficiency at or above New York Heart Association (NYHA) class II;

      * History of clinically significant ventricular arrhythmias (such as persistent ventricular tachycardia, ventricular fibrillation, and torsade de pointes) or frequent and uncontrollable arrhythmias;

        * Unstable angina pectoris, or severe stenosis and occlusion of the coronary artery;

          * Suffered from myocardial infarction within 6 months;

            * The Fridericia-corrected QT interval (QTcF) is greater than 450 milliseconds (msec) for males and greater than 470 msec for females (if QTc is abnormal, it can be continuously measured three times with an interval of more than 2 minutes, and the average value can be taken);

              * History or family history of congenital long QT syndrome;
  * Presence of uncontrolled infection of ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 14 days prior to the commencement of study treatment;
  * Subjects with a history of interstitial lung disease/pneumonia (non-infectious) requiring steroid intervention, or currently accompanied by interstitial lung disease/pneumonia, or subjects with suspected interstitial lung disease/pneumonia indicated by imaging during the screening period and unable to be excluded;
  * Subjects with moderate to severe pulmonary dysfunction/disease within 3 months prior to the first dose, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/obstructive bronchiolitis, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, etc.; subjects with active tuberculosis, drug-induced pneumonia, radiation pneumonia requiring treatment, or clinically symptomatic active pneumonia during the screening period; and subjects with any autoimmune, connective tissue, or inflammatory diseases involving the lungs (rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or those who have previously undergone unilateral pneumonectomy, etc.;
  * Subjects with active viral hepatitis and poor control. Subjects who meet the following requirements can be screened: HBsAg-positive subjects must meet the criteria of Hepatitis B Virus (HBV) DNA quantification \<2000 IU/ml (or 1\*104 copy/ml) or have received anti-HBV treatment for at least 1 week before the start of the study and have a 10-fold (1 log value) or greater reduction in viral index, and the subjects are willing to receive anti-HBV treatment throughout the entire study period; HCV-infected subjects (HCV Ab or HCV RNA positive): subjects who are judged by the investigator to be in a stable state or are currently undergoing antiviral treatment at the time of enrollment and continue to receive approved antiviral treatment during the study;
  * Individuals with active syphilis infection requiring treatment;
  * Those who are preparing for or have previously undergone allogeneic bone marrow transplantation or solid organ transplantation;
  * Subjects who require immunosuppressive agents, systemic or absorbable local hormone therapy for immunosuppression, and still need to continue using them within 7 days before the first administration (excluding subjects with a daily dose of \<10 mg prednisone or other equally effective hormones);
  * History of immune deficiency, including HIV positivity or other acquired or congenital immune deficiency diseases;
  * Patients with renal failure requiring hemodialysis or peritoneal dialysis; or those who have previously had or currently have nephrotic syndrome (excluding those who have been cured) or chronic nephritis;
  * Poorly controlled diabetes (fasting blood glucose (FBG) \> 10 mmol/L);
  * Those who suffer from epilepsy and require treatment;
  * Individuals with a history of abuse of psychotropic drugs and unable to quit, or those with severe mental disorders.
* Tumor-related symptoms and treatment:

  * There has been moderate to large amounts of pleural effusion, ascites, and pericardial effusion in the past 2 weeks;
  * Patients with cancerous lymphangitis;
  * Tumor invasion of major blood vessels;
  * Patients who have received intravenous chemotherapy, radiotherapy, immunotherapy, biotherapy, or macromolecular targeted therapy for anti-tumor treatment within 3 weeks before the start of the study treatment, or who have received endocrine therapy, small molecule targeted drugs, or oral chemotherapy within 2 weeks before the start of the study treatment, the washout period is calculated from the end of the last treatment;
  * Patients who have received treatment with traditional Chinese patent medicines and simple preparations (including but not limited to Compound Cantharidin Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Brucea javanica oil injection/capsules, Xiaocaiping Tablets/Injection, Huachansu Capsules, etc.) with clear anti-tumor indications specified in the National Medical Products Administration (NMPA) -approved drug instructions within 2 weeks before the start of the study treatment.
* Research treatment-related

  * Previously received ADC therapy using a topoisomerase 1 inhibitor as the toxin during the recurrence or metastasis stage, or experienced recurrence or metastasis within 12 months after neoadjuvant/adjuvant therapy (excluding cohort 5 in the extension stage);
  * Allergic to any research drug or any ingredient or adjuvant in the drug; 39. 3) Individuals who have experienced severe hypersensitivity reactions after the use of monoclonal antibodies;
  * Subjects who have received treatment with other anti-tumor drugs in clinical trials within 4 weeks prior to the start of the study treatment, if the clinical study involves a marketed drug, shall be excluded according to exclusion criterion 4.2).
* According to the researcher's judgment, there are situations that seriously endanger the safety of the subjects or affect their ability to complete the study.