Milaberon in Advanced Solid Tumors: an Open, Multicenter Clinical Study

Inclusion Criteria:

• Patients voluntarily participate in the study, sign informed consent, and have goodcompliance;

• 18-65 years old (including 18 and 65 years old);

• solid tumors confirmed by histology and/or cytology, and advanced metastatic tumorsthat are not feasible for surgical resection;

• Has not received previous systemic antitumor drug therapy for metastatic/recurrentsolid tumors;

• For subjects who have previously received neoadjuvant/adjuvant therapy, it takesmore than 6 months from the last treatment to relapse or progression;

• Recovery of previous treatment-related AEs to National Cancer Institute TerminologyCriteria for Common Adverse Events (NCI-CTCAE)≤ Grade 1 (excluding alopecia);

• According to RECIST 1.1 standard, there is at least one measurable lesion assessedby the research center, and the measurable lesion should be a lesion that has notreceived local treatment such as radiotherapy (the lesion located in the region ofprevious radiotherapy can also be regarded as a measurable lesion that meets therequirements if progress is confirmed);

• ECOG physical condition: 0-1;

• Expected survival ≥ 12 weeks;

• The function of major organs is normal, I .e. the following criteria are met (noblood transfusion, albumin, recombinant human thrombopoietin or colony stimulatingfactor [CSF] treatment has been received within 14 days before the first study drugadministration): blood test (absolute value of neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin concentration ≥ 9g/dL); Liver function test (bilirubin ≤ 1.5 × ULN; aspartate aminotransferase and glutamate aminotransferase ≤ 2.5 ×ULN, ASTand ALT ≤ 5 ×ULN in case of liver metastasis); renal function (serum creatinine ≤ 1.5 ×ULN, or creatinine clearance rate (CCr)≥ 60 ml/min); coagulation function,international normalized ratio (INR)≤ 1.5 ×ULN, prothrombin time (PT) and activatedpartial thromboplastin time (APTT)≤ 1.5 ×ULN; thyroid function, thyroid-stimulatinghormone (TSH)≤ the upper limit of normal (ULN); FT3 and FT4 levels should beexamined if abnormal, and FT3 and FT4 levels are normal; (11) Women of childbearingage must have a negative serum pregnancy test within 14 days prior to treatment andbe willing to use medically approved effective contraception during the study periodand within 3 months after the last dose of study medication (e. g. IUDs,contraceptives or condoms; surgical sterilization is required for male subjectswhose partner is a woman of childbearing age, alternatively, an effective method ofcontraception is recommended for the duration of the study and for 3 months afterthe last study dose.

Exclusion Criteria:

• Received the following treatment within 4 weeks before treatment: radiotherapy oftumor, major surgical operation or wound has not been completely healed, β3adrenoceptor agonist and corresponding clinical research drugs;

• those who have contraindications to Miraberon: those who are allergic to Miraberonor any of its excipients;

• Active malignant tumors in the past 3 years, except for tumors participating in thestudy and local tumors that have been cured, such as skin basal cell carcinoma, skinsquamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ,breast carcinoma in situ, etc;

• symptomatic brain or meningeal metastases; Severe infection (such as intravenousinfusion of antibiotics, antifungals, or antivirals) within 4 weeks beforetreatment, or fever of unknown origin> 38.5°C during screening/first dose;

• have high blood pressure that cannot be well controlled by antihypertensive drugtherapy (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg);

• Within 3 months before treatment, there were obvious clinical bleeding symptoms orobvious bleeding tendency (bleeding> 30 mL within 3 months, hematemesis, blackstool, hematochezia), hemoptysis (fresh blood> 5 mL within 4 weeks), etc. or avenous/venous thrombotic event within 6 months prior to treatment, such as acerebrovascular accident (including transient ischemic attack, cerebral hemorrhage,cerebral infarction), deep vein thrombosis, and pulmonary embolism; or the need forlong-term anticoagulant therapy with warfarin or heparin, or the need for long-termantiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day);

• The tumor is found to invade large vascular structures during screening, such aspulmonary artery, superior vena cava or inferior vena cava, and the researchersjudge that there is a greater risk of bleeding;

• Active heart disease, including myocardial infarction, severe/unstable anginapectoris, 6 months before treatment. Echocardiography left ventricular ejectionfraction <50%, arrhythmia poorly controlled;

• Uncontrollable pleural effusion, pericardial effusion or ascites requiring frequentdrainage after appropriate intervention;

• Presence of any active autoimmune disease or history of autoimmune disease,including but not limited to: autoimmune hepatitis, interstitial pneumonia,pulmonary fibrosis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis,nephritis, thyroid function progression, decreased thyroid function; Note:(1)Subjects whose thyroid function can only be controlled by hormone replacementtherapy can be included;(2) Subjects with skin diseases that do not require systemictreatment, such as vitiligo, psoriasis, alopecia, type 1 diabetes, or childhoodasthma has been completely resolved, and no intervention can be included afteradulthood;(3) Patients with asthma who require medical intervention withbronchodilators cannot be included;

• received treatment with live attenuated vaccine within 28 days prior to the firstadministration of the study drug;

• The patient has a known history of psychotropic substance abuse, alcohol abuse ordrug abuse; a history of definite neurological or psychiatric disorders, includingepilepsy or dementia

• tuberculosis infection history;

• known human immunodeficiency virus (HIV) infection;

• Known history of clinically significant liver disease, including viral hepatitis [Known hepatitis B virus (HBV) carriers must exclude active HBV infection, I .e.,HBV DNA positive (>1 × 104 copies/mL or> 2000 IU/mL);

• Known hepatitis C virus infection (HCV) and HCV RNA positive (>1 x 103 copies/mL),or other hepatitis, cirrhosis];

• Patients with renal injury: GFR<30 mL/min 1.73m2 or patients requiring hemodialysis

• any other medical condition, clinically significant metabolic, physical, orlaboratory abnormality, which, in the investigator's judgment, would reasonablysuspect that the patient has a disease or condition that is not appropriate for thestudy drug (e. g., having seizures requiring treatment, bladder outlet obstruction,anxiety), or would interfere with the interpretation of the study results, or placethe patient in a high-risk situation, or patients considered by the investigator tobe unsuitable for inclusion.