IMM2510, a PD-L1 and VEGF Bispecific Fusion Protein, in Patients With Advanced Solid Tumors

Inclusion Criteria:

1. Subjects must voluntarily sign the informed consent form; they were able tocommunicate well with the investigator and comply with the study requirements.
2. Age ≥ 18 years old.
3. Advanced solid tumors confirmed by histology or cytology, failed standard therapy, nostandard therapy, or unable to tolerate current standard therapy.
4. Presence of at least one measurable tumor lesion (according to RECIST 1.1 criteria),defined as the maximum longest diameter of 10 mm for imaging (CT/MRI) or 15 mm for asingle pathological lymph node lesion; the presence of at least one evaluable tumorlesion is allowed in the dose escalation phase.
5. Life expectancy of at least 3 months.
6. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
7. Organ or bone marrow function must meet the following criteria:
8. Hematology (no blood component or cell growth factor was used to support therapywithin 7 days prior to study treatment): absolute neutrophil count ≥ 1.5×109/L;Hemoglobin ≥ 90 g/L; Platelet count ≥ 100×109/L.
9. Serum total bilirubin ≤ 1.5× upper limit of normal (ULN) (unless Gilbert syndromeis confirmed); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN; ALT and AST were ≤ 5.0×ULN when the elevation was judged to bedue to liver metastasis.
10. Prothrombin time (PT) ≤ 1.2×ULN, partial prothrombin kinase time (APTT) ≤ 1.2×ULN; International Standardized ratio (INR) ≤ 1.2 (unless receiving warfarintreatment); After 2 weeks of oral anticoagulant therapy, the dose is stable. Ifwarfarin is taken orally, the patient must have an INR ≤ 2.5 and no bleeding.
11. Endogenous creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula), urinaryprotein < 2+ or protein quantity < 1.0 g.
12. Left ventricular ejection fraction (LVEF) ≥50%.
13. Toxicity of previous treatment has been restored to grade 1 [NCI CTCAE 5.0 gradingstandard was adopted] (except for hair loss and chemotherapy-induced neurotoxicity ≤grade 2 and other toxicity judged by researchers to be without safety risk).
14. Women and men of childbearing age must agree, after signing an informed consent form,to use effective contraception during the study period and within three months afterthe final dose, and women of childbearing age must have a negative pregnancy testresult 72 hours before the dose.
15. The patient is willing and able to comply with protocol visits, treatment protocols,laboratory tests, and other requirements of the study.

Exclusion Criteria:

1. Enrol in another clinical study at the same time, unless it is an observational,non-interventional clinical study or the follow-up period of an interventional study.
2. Received the last systemic antitumor therapy, including chemotherapy, immunotherapy,and biological agents, within 3 weeks before the first administration; Receivedhormone antitumor therapy and small-molecule targeted therapy within 2 weeks beforethe first administration; Palliative local therapy was performed for non-targetlesions within 2 weeks before the first administration; Nonspecific immunomodulatorytherapy (e.g., interleukin, interferon, thymosin, tumor necrosis factor, not IL-11 forthrombocytopenia) was administered within 2 weeks prior to initial administration;Received Chinese herbal medicine or Chinese patent medicine with anti-tumorindications within 1 week prior to initial administration.
3. Patients with active central nervous system (CNS) metastasis, but the followingpatients were admitted: a. Treated patients with brain metastases (such as surgery andradiotherapy), stable for at least 2 weeks after treatment (before the firstadministration of the study drug), no evidence of new metastatic lesions or metastaticlesion enlargement, and corticosteroid withdrawal ≥3 days before the study drugadministration; b. Untreated, asymptomatic subjects with brain metastases who do notrequire corticosteroids and whose brain metastases are no more than 1.5 cm in length.
4. Receiving >1 programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors,such as pembrolimab, opdivo, Atzumab, or Devarumab, or > 1 anti-angiogenesisinhibitor, such as bevacizumab, ramolumab, Apatinib, or Regofenib; Or receivedPD-1/PD-L1 inhibitors and antiangiogenic inhibitors at the same time (includingdifferent time sequences of therapy).
5. Developed other malignant tumors within 5 years prior to enrollment. Exceptions: 1)cured cervical carcinoma in situ and non-melanoma skin cancer; 2) Patients withradical treatment, unless they had a complete response for at least 2 years prior toenrollment and did not require additional treatment or did not require additionaltreatment during the study period.
6. Active, known secondary primary cancer that has not recurred within five years;Exceptions: 1) Both primary and secondary cancers were considered to benefit from thisstudy; 2) The investigators have clearly ruled out which primary tumor source themetastases belong to.
7. History of autoimmune diseases, including but not limited to systemic lupuserythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease,Hashimoto's thyroiditis, autoimmune thyroid disease, multiple sclerosis, etc. Exceptthe following diseases, they are allowed to be included in the group:

• Hypothyroidism that can be controlled with hormone replacement therapy alone
• Skin diseases that do not require systemic treatment (e.g. Vitiligo, psoriasis)
• Celiac disease under control.

8. Patients who had received major surgery within 4 weeks before enrollment; Had receivedminor surgical procedures (including catheterization, but not peripheral venipuncturecentral venous catheterization) within 2 days before enrollment.
9. High blood pressure that medications fail to control (systolic blood pressure 140mmHgand/or diastolic blood pressure 90mmHg) or pulmonary hypertension or unstable anginapectoris; Previous myocardial infarction or bypass grafting or stent surgery within 6months prior to drug administration; History of chronic heart failure with the NewYork Heart Association (NYHA) criteria of Grade 3-4; Clinically significant valvulardisease; Severe arrhythmias requiring treatment (except atrial fibrillation,paroxysmal supraventricular tachycardia), Including QTcF 450ms for men and 470ms forwomen (calculated by Fridericia formula); Cerebrovascular accident (CVA) or transientischemic attack (TIA) within 12 months before enrollment.
10. History of arterial thrombosis, deep vein thrombosis and pulmonary embolism within 6months prior to enrollment.
11. Patients with skin wounds, surgical sites, wound sites, mucous membrane ulcers orfractures that are not fully healed were judged by the researchers to be at risk ofbleeding when participating in the study.
12. Conditions that may cause bleeding or perforation of the digestive tract (e.g.duodenal ulcer, intestinal obstruction, acute Crohn's disease, ulcerative colitis,extensive removal of the stomach and small intestine, etc.); Patients with chronicCrohn's disease and ulcerative colitis (except for total colon and rectal excision)should be excluded even during inactive periods; Hereditary nonpolyposis colorectalcancer or familial adenomatous polyposis syndrome; Patients with past history ofintestinal perforation and intestinal fistula, but not cured after surgical treatment;Esophageal and gastric varices.
13. Present or past symptoms of idiopathic pulmonary fibrosis or idiopathic pneumonia;Acute lung disease, interstitial lung disease or pneumonia (except local interstitialpneumonia induced by radiotherapy), pulmonary fibrosis, etc.; Patients with severedyspnea, pulmonary insufficiency or continuous oxygen inhalation.
14. Uncontrolled fluid with repeated drainage or obvious symptoms in the chest, abdomenand pericardium.
15. Subjects who required systemic corticosteroid (dose equivalent to > 10 mg/day ofprednisone) or other immunosuppressive drug treatment within 14 days prior toenrollment or during the study period; The following conditions allow inclusion:

• Subjects are permitted to use topical or inhaled corticosteroids
• Short-term (≤ 7 days) use of glucocorticoids is permitted for the prevention ortreatment of non-autoimmune allergic diseases

16. Patients who were severely infected within the first 4 weeks of enrollment, or who hadany signs or symptoms of active infection within the first 2 weeks, or who requiredantibiotic therapy within the first 2 weeks (except for prophylactic antibiotics);Unexplained fever > 38.5℃ before the first administration (the subjects could beenrolled if their fever was due to tumor, according to the investigators).
17. People infected with active tuberculosis.
18. History of organ transplantation or hematopoietic stem cell transplantation.
19. History of human immunodeficiency virus (HIV) infection or other acquired orcongenital immunodeficiency diseases.
20. Hepatitis B surface antigen (HBs-Ag) positive, and HBV-DNA ≥ 2000 IU/mL or beyond thenormal line; Hepatitis C (HCV) ribonucleic acid (RNA) positive.
21. Attenuated vaccine is expected to be given 4 weeks before administration, duringtreatment or within 30 days of the last administration.
22. Patients with previous severe allergic reactions to macromolecular proteinpreparations/monoclonal antibodies.
23. Permanent discontinuation of the drug due to immune-related toxicity during previousantitumor immunotherapy.
24. Poor compliance with a clear past history of neurological or psychiatric disorders,such as epilepsy, dementia, or alcohol, drug or substance abuse.
25. Other conditions deemed unsuitable for participation in this clinical trial by theinvestigator.