Study of AK105 With Anlotinib and Radiotherapy Adjuvant Therapy in MGMT Unmethylated Newly Diagnosed Glioblastoma.

Inclusion Criteria:

• The patient voluntarily joined the study and signed a written informed consent;
• Pathologically confirmed treatment-naïve glioblastoma with PCR tested MGMTunmethylated;
• The interval between the last biopsy or surgery is 4-6 weeks, and the surgicalincision is healed well;
• According to Rano criteria, there are evaluable measurable disease;
• 18-70 years of age;
• Karnofsky performance status (KPS) ≥ 60; and estimated survival of at least 3 months;
• The main organ function to meet the following criteria:

1. routine blood test: HB≥90g/L(no blood transfusion in 14 days); ANC≥1.5×109/L; Whiteblood cell counts≥3.5×109/L; PLT≥90×109/L; 2) blood biochemical test: ALT and AST ≤2.5×ULN(times the upper limit of normal) and if liver/bone metastases≤5×ULN; TBIL ≤1.5 ULN; Serum Cr≤1.5×ULN and CrCL≥60 ml/min; 3) APTT, INR and PT≤1.5×ULN;

• The woman patients of childbearing age who must agree to take contraceptive methodsduring the research and within another 6 months after it; who are not in the lactationperiod and examined as negative in blood serum test or urine pregnancy test within 7days before the research.

Exclusion Criteria:

• Prior therapy with anti-angiogenic drugs, such as anlotinib, apatinib, lenvatinib,sorafenib, sunitinib, surufatinib, regorafenib or fruquintinib ect, or withanti-PD-1(L1) or anti-CTLA-4 agents;
• Patients who get other monoclonal antibodies have severe hypersensitivity;
• Present or along with other malignancies within 5 years. Exceptions include curedbasal cell carcinoma of the skin or in situ prostate cancer or in situ cervicalcancer;
• Patients have any active autoimmune disease that required systemic treatment,including but not limited to autoimmune hepatitis, enteritis, vasculitis, nephritis;asthma that require bronchodilators for medical intervention. Exceptions includepatients with vitiligo, psoriasis, alopecia or well-controlled type 1 diabetes but notrequired systemic treatment, or hypothyroidism with normal thyroid function afteralternative treatment;
• In the past, there is a treatment toxicity of CTCAE5.0 ≥2 grade that has not beencompletely relieved (the adverse reaction grades in this article, unless otherwisespecified, are defaulted to the CTCAE 5.0 standard);
• Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (>10mg/dayprednisone or equivalent) or any other form of immunosuppressive therapy, andcontinued to be used within 2 weeks before the first dose in this study;
• Those with multiple factors affecting oral drugs (such as inability to swallow, postgastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.);
• Imaging (CT or MRI) shows that the tumor has invaded or unclearly separated the largeblood vessels;
• Patients with active bleeding, or unexplained persistent decline in hemoglobin shouldpostpone their screening/enrollment until the bleeding stops and the investigatorjudges it to be safe;
• Within 4 weeks before the first dose in this study, patients with CTCAE5.0 grade 3+bleeding; patients treated with anticoagulants or vitamin K antagonists such aswarfarin, heparin or their analogues; on the premise that the international normalizedratio of prothrombin time (INR) ≤1.5, it is allowed to use low-dose warfarin (≤1mg/D),low-dose heparin (≤12000U /D) or low-dose aspirin (≤100mg/D) for preventive purposes;
• Within 4 weeks before the first dose in this study, patients with unhealed wounds,fractures, gastric and duodenal active ulcers, ulcerative colitis, or unresectedtumors have active bleeding, or may be caused as determined by the researchers otherconditions of gastrointestinal bleeding and perforation, have undergone major surgery (excluding vascular access surgery), inoculated with preventive vaccine or attenuatedvaccine;
• Received the treatment of proprietary Chinese medicines with anti-tumor indicationsspecified in the NMPA approved drug instructions within 2 weeks before the start ofthe study treatment(Including compound cantharidin capsules, Kangai injection,Kanglaite capsule/injection, Aidi injection, brucea javanica oil injection/capsule,Xiaoaiping tablet/injection, Huachansu capsule, etc.); or received drugs withimmunomodulatory effects (including thymosin, interferon, and interleukin, except forlocal use to control pleural effusion or ascites);
• History of organ or blood transplantation;
• Patients have active diverticulitis, abdominal abscess, gastrointestinal obstruction;
• Patients with any severe and/or uncontrollable disease, including:

1. Patients with unsatisfactory blood pressure control (systolic blood pressure>140mmHg, diastolic blood pressure>90 mmHg); 2)Within 6 months of the first administrationpatients with myocardial ischemia or myocardial infarction, arrhythmia that requiretreatment (including QTC ≥480ms), and grade ≥2 congestive heart failure; 3) active oruncontrolled serious infection (≥CTCAE5.0 Grade 2 infection), tuberculosis patients;
2. Known clinical history of liver disease, including viral hepatitis, carriers ofhepatitis b virus must be excluded from active HBV infection, i.e., HBV DNA positive (>2500 copy /mL or >500IU/mL);known hepatitis c virus infection (HCV) and HCV RNApositive (>1 x 10^3 copy /mL), or other decompensated liver disease, chronic hepatitisrequires antiviral treatment; 5) HIV test positive or Syphilis Testing RPR positive;
3. Diabetes is poorly controlled (fasting blood glucose (FBG) ≥10mmol/L); 7) Urineroutines suggest that urine protein is ≥++, and the 24-hour urine proteinquantification is more than 1.0 g;

• Those considered by the researcher to be unsuitable for inclusion.