{
    "info": {
        "nct_id": "NCT03910127",
        "official_title": "A Phase Ib, Multicenter, Randomized Study to Evaluate the Pharmacokinetics, Efficacy and Safety of TQB2450 Combined With or Without Anlotinib in Patients With Advanced Non-small Cell Lung Cancer（NSCLC）",
        "inclusion_criteria": "1.18 years and older; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; Life expectancy ≥ 3 months.\n\n2. Histologically or cytologically confirmed Epidermal Growth Factor Receptor (EGFR)/ Anaplastic Lymphoma Kinase (ALK) wild type non-small cell lung cancer.\n\n3. Advanced patients who had received at least first-line of standard chemotherapy but failed or intolerable , with at least one measurable lesion based on RECIST 1.1.\n\n4. PD-L1-positive tumor status (TPS≥1%) as determined by an immunohistochemistry (IHC) assay based on PD-L1 expression on tumor infiltrating immune cells and/or tumor cells performed by a central laboratory.\n\n5.The main organs function are normally, the following criteria are met:\n\n1. routine blood tests：hemoglobin (Hb)≥90g/L (no blood transfusion and blood products within 14 days); absolute neutrophil count (ANC) ≥1.5×109/L; platelets (PLT) ≥80×109/L;\n2. Blood biochemical examination: alanine transaminase (ALT) and aspartate aminotransferase (AST)≤ 2.5×ULN (when the liver is invaded，≤ 5×ULN);total bilirubin (TBIL)≤1.5×ULN (Gilbert syndrome patients，≤ 3×ULN)；serum creatinine (Cr) ≤1.5×ULN，or calculated creatinine clearance (CrCl) ≥50ml/min； calculated creatinine clearance formula：Ccr=(140-age)×weight(kg)/72×Scr(mg/dl) Ccr=[(140-age)×weight(kg)]/[0.818×Scr(umol/L) (According to the calculation results , female Patients ×0.85；1 mg/dL = 88.41 umol/ L)\n3. Coagulation function: activated partial thromboplastin time (aPTT) ,international normalized ratio (INR) ,prothrombin time (PT) ≤1.5×ULN；\n4. left ventricular ejection fraction (LVEF) measured by the Cardiac echocardiography ≥ 50%.\n\n   6. Male or female subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study (such as intrauterine devices , contraceptives or condoms) ；No pregnant or breastfeeding women, and a negative pregnancy test are received within 7 days before the randomization.\n\n   7. Understood and signed an informed consent form.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "1. Prior therapy with Anlotinib, anti-programmed cell death (PD)-1, anti-PD-L1 or other immunotherapy against PD-1/PD-L1.\n2. Severe hypersensitivity occurs after administration of other monoclonal antibodies.\n3. Diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of cured basal cell carcinoma of skin and carcinoma in situ of cervix.\n4. Has any active autoimmune disease or history of autoimmune disease, such as autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis, asthma patients who need bronchiectasis for medical intervention; Subjects with the vitiligo without systemic treatment, psoriasis, alopecia, well-controlled type I diabetes mellitus, hypothyroidism stable on hormone replacement will not be excluded from this study.\n5. Immunosuppressive therapy with immunosuppressive agents or systemic or absorbable local hormones (dosage > 10 mg/day prednisone or other therapeutic hormones) is required for the purpose of immunosuppression.\n6. Has multiple factors affecting oral medication, such as inability to swallow, post-gastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.\n7. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.\n8. Imaging (CT or MRI) shows that tumor invades large blood vessels or the boundary with blood vessels is unclear.\n9. Has any bleeding or bleeding events ≥ grade 3 or with unhealed wounds, ulcerative , or fractures within 4 weeks prior to the first administration.\n10. Has uncontrollable symptoms of brain metastases, spinal cord compression, cancerous meningitis within 8 weeks before the first-dosing, or brain or leptomeningeal disease found by CT or MRI during screening.\n11. Has received chemotherapy, surgery, radiotherapy, the last treatment from the first dose less than 4 weeks, or oral targeted drugs for less than 5 half-lives, or oral fluorouracil pyridine drugs for less than 14 days, mitomycin C and nitrosourea for less than 6 weeks. Patients whose adverse events (except alopecia) caused by previous treatment did not recover to ≤ grade 1.\n12. Patients with any serious and/or uncontrollable disease, including :\n\n    1. Has poor blood pressure control, systolic blood pressure ≥ 150 mmHg, diastolic blood pressure ≥ 90 mmHg;\n    2. Thrombotic events, ischemic attacks, myocardial infarction, grade 2 congestive heart failure or arrhythmias requiring treatment including QTc ≥ 480ms occurred within 6 months of first administration;\n    3. Severe active or uncontrolled infections ≥ grade 2;\n    4. Has known clinical history of liver diseases, including viral hepatitis, known carriers of hepatitis B virus (HBV) must exclude active HBV infection, that is, HBV DNA positive > 1 *104 copies/mL or > 2000 IU/mL, known hepatitis C virus infection (HCV) and HCV RNA positive > 1 *103 copies/mL, or other decompensated hepatitis and chronic hepatitis, which require antiviral treatment;\n    5. HIV positive;\n    6. Poor control of diabetes mellitus, fasting blood-glucose ≥ grade 2;\n13. Has vaccinated with vaccines or attenuated vaccines within 4 weeks prior to first administration.\n14. According to the judgement of the researchers, there are other factors that may lead to the termination of the study.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "1.18 years and older; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; Life expectancy ≥ 3 months.",
            "criterions": [
                {
                    "exact_snippets": "18 years and older",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "range",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 0,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 1,
                                        "unit": "N/A"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Life expectancy ≥ 3 months",
                    "criterion": "life expectancy",
                    "requirements": [
                        {
                            "requirement_type": "minimum duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Histologically or cytologically confirmed Epidermal Growth Factor Receptor (EGFR)/ Anaplastic Lymphoma Kinase (ALK) wild type non-small cell lung cancer.",
            "criterions": [
                {
                    "exact_snippets": "Histologically or cytologically confirmed",
                    "criterion": "confirmation method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "histologically",
                                "cytologically"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Epidermal Growth Factor Receptor (EGFR) ... wild type",
                    "criterion": "EGFR status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "wild type"
                        }
                    ]
                },
                {
                    "exact_snippets": "Anaplastic Lymphoma Kinase (ALK) wild type",
                    "criterion": "ALK status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "wild type"
                        }
                    ]
                },
                {
                    "exact_snippets": "non-small cell lung cancer",
                    "criterion": "cancer type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "non-small cell lung cancer"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Advanced patients who had received at least first-line of standard chemotherapy but failed or intolerable , with at least one measurable lesion based on RECIST 1.1.",
            "criterions": [
                {
                    "exact_snippets": "Advanced patients",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "advanced"
                        }
                    ]
                },
                {
                    "exact_snippets": "received at least first-line of standard chemotherapy",
                    "criterion": "chemotherapy treatment",
                    "requirements": [
                        {
                            "requirement_type": "treatment line",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "line"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "failed or intolerable",
                    "criterion": "response to chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "response",
                            "expected_value": [
                                "failed",
                                "intolerable"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "at least one measurable lesion based on RECIST 1.1",
                    "criterion": "measurable lesion",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "lesion"
                            }
                        },
                        {
                            "requirement_type": "measurement standard",
                            "expected_value": "RECIST 1.1"
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. PD-L1-positive tumor status (TPS≥1%) as determined by an immunohistochemistry (IHC) assay based on PD-L1 expression on tumor infiltrating immune cells and/or tumor cells performed by a central laboratory.",
            "criterions": [
                {
                    "exact_snippets": "PD-L1-positive tumor status (TPS≥1%)",
                    "criterion": "PD-L1-positive tumor status",
                    "requirements": [
                        {
                            "requirement_type": "TPS",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "as determined by an immunohistochemistry (IHC) assay",
                    "criterion": "immunohistochemistry (IHC) assay",
                    "requirements": [
                        {
                            "requirement_type": "determination",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "based on PD-L1 expression on tumor infiltrating immune cells and/or tumor cells",
                    "criterion": "PD-L1 expression",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "tumor infiltrating immune cells",
                                "tumor cells"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "performed by a central laboratory",
                    "criterion": "central laboratory",
                    "requirements": [
                        {
                            "requirement_type": "performance",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "5.The main organs function are normally, the following criteria are met:",
            "criterions": [
                {
                    "exact_snippets": "The main organs function are normally",
                    "criterion": "main organ function",
                    "requirements": [
                        {
                            "requirement_type": "functionality",
                            "expected_value": "normal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. routine blood tests：hemoglobin (Hb)≥90g/L (no blood transfusion and blood products within 14 days); absolute neutrophil count (ANC) ≥1.5×109/L; platelets (PLT) ≥80×109/L;",
            "criterions": [
                {
                    "exact_snippets": "hemoglobin (Hb)≥90g/L",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 90,
                                "unit": "g/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "no blood transfusion and blood products within 14 days",
                    "criterion": "blood transfusion",
                    "requirements": [
                        {
                            "requirement_type": "absence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "absolute neutrophil count (ANC) ≥1.5×109/L",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "×10^9/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "platelets (PLT) ≥80×109/L",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 80,
                                "unit": "×10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Blood biochemical examination: alanine transaminase (ALT) and aspartate aminotransferase (AST)≤ 2.5×ULN (when the liver is invaded，≤ 5×ULN);total bilirubin (TBIL)≤1.5×ULN (Gilbert syndrome patients，≤ 3×ULN)；serum creatinine (Cr) ≤1.5×ULN，or calculated creatinine clearance (CrCl) ≥50ml/min； calculated creatinine clearance formula：Ccr=(140-age)×weight(kg)/72×Scr(mg/dl) Ccr=[(140-age)×weight(kg)]/[0.818×Scr(umol/L) (According to the calculation results , female Patients ×0.85；1 mg/dL = 88.41 umol/ L)",
            "criterions": [
                {
                    "exact_snippets": "alanine transaminase (ALT) ... ≤ 2.5×ULN (when the liver is invaded，≤ 5×ULN)",
                    "criterion": "alanine transaminase (ALT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "aspartate aminotransferase (AST)≤ 2.5×ULN (when the liver is invaded，≤ 5×ULN)",
                    "criterion": "aspartate aminotransferase (AST)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "total bilirubin (TBIL)≤1.5×ULN (Gilbert syndrome patients，≤ 3×ULN)",
                    "criterion": "total bilirubin (TBIL)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 1.5,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "serum creatinine (Cr) ≤1.5×ULN",
                    "criterion": "serum creatinine (Cr)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 1.5,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "calculated creatinine clearance (CrCl) ≥50ml/min",
                    "criterion": "calculated creatinine clearance (CrCl)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 50,
                                        "unit": "ml/min"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Coagulation function: activated partial thromboplastin time (aPTT) ,international normalized ratio (INR) ,prothrombin time (PT) ≤1.5×ULN；",
            "criterions": [
                {
                    "exact_snippets": "activated partial thromboplastin time (aPTT) ... ≤1.5×ULN",
                    "criterion": "activated partial thromboplastin time (aPTT)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "international normalized ratio (INR) ... ≤1.5×ULN",
                    "criterion": "international normalized ratio (INR)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "prothrombin time (PT) ≤1.5×ULN",
                    "criterion": "prothrombin time (PT)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. left ventricular ejection fraction (LVEF) measured by the Cardiac echocardiography ≥ 50%.",
            "criterions": [
                {
                    "exact_snippets": "left ventricular ejection fraction (LVEF) ... ≥ 50%",
                    "criterion": "left ventricular ejection fraction (LVEF)",
                    "requirements": [
                        {
                            "requirement_type": "measurement",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Male or female subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study (such as intrauterine devices , contraceptives or condoms) ；No pregnant or breastfeeding women, and a negative pregnancy test are received within 7 days before the randomization.",
            "criterions": [
                {
                    "exact_snippets": "Male or female subjects should agree to use an adequate method of contraception",
                    "criterion": "contraception use",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "No pregnant or breastfeeding women",
                    "criterion": "pregnancy or breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "a negative pregnancy test are received within 7 days before the randomization",
                    "criterion": "pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Understood and signed an informed consent form.",
            "criterions": [
                {
                    "exact_snippets": "Understood and signed an informed consent form",
                    "criterion": "informed consent form",
                    "requirements": [
                        {
                            "requirement_type": "understanding",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "signature",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "2. Severe hypersensitivity occurs after administration of other monoclonal antibodies.",
            "criterions": [
                {
                    "exact_snippets": "Severe hypersensitivity occurs after administration of other monoclonal antibodies.",
                    "criterion": "hypersensitivity",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "trigger",
                            "expected_value": "administration of other monoclonal antibodies"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of cured basal cell carcinoma of skin and carcinoma in situ of cervix.",
            "criterions": [
                {
                    "exact_snippets": "Diagnosed and/or treated additional malignancy within 5 years prior to randomization",
                    "criterion": "additional malignancy",
                    "requirements": [
                        {
                            "requirement_type": "diagnosis",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "years"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "cured basal cell carcinoma of skin",
                    "criterion": "basal cell carcinoma of skin",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "cured"
                        }
                    ]
                },
                {
                    "exact_snippets": "carcinoma in situ of cervix",
                    "criterion": "carcinoma in situ of cervix",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "cured"
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Has any active autoimmune disease or history of autoimmune disease, such as autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis, asthma patients who need bronchiectasis for medical intervention; Subjects with the vitiligo without systemic treatment, psoriasis, alopecia, well-controlled type I diabetes mellitus, hypothyroidism stable on hormone replacement will not be excluded from this study.",
            "criterions": [
                {
                    "exact_snippets": "Has any active autoimmune disease or history of autoimmune disease",
                    "criterion": "autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "autoimmune hepatitis",
                    "criterion": "autoimmune hepatitis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "interstitial pneumonia",
                    "criterion": "interstitial pneumonia",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "enteritis",
                    "criterion": "enteritis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "vasculitis",
                    "criterion": "vasculitis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "nephritis",
                    "criterion": "nephritis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "asthma patients who need bronchiectasis for medical intervention",
                    "criterion": "asthma requiring bronchiectasis for medical intervention",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "vitiligo without systemic treatment",
                    "criterion": "vitiligo without systemic treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "psoriasis",
                    "criterion": "psoriasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "alopecia",
                    "criterion": "alopecia",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "well-controlled type I diabetes mellitus",
                    "criterion": "well-controlled type I diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "hypothyroidism stable on hormone replacement",
                    "criterion": "hypothyroidism stable on hormone replacement",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Immunosuppressive therapy with immunosuppressive agents or systemic or absorbable local hormones (dosage > 10 mg/day prednisone or other therapeutic hormones) is required for the purpose of immunosuppression.",
            "criterions": [
                {
                    "exact_snippets": "Immunosuppressive therapy with immunosuppressive agents or systemic or absorbable local hormones",
                    "criterion": "immunosuppressive therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "dosage > 10 mg/day prednisone or other therapeutic hormones",
                    "criterion": "hormone dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 10,
                                "unit": "mg/day"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Has multiple factors affecting oral medication, such as inability to swallow, post-gastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.",
            "criterions": [
                {
                    "exact_snippets": "inability to swallow",
                    "criterion": "ability to swallow",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "post-gastrointestinal resection",
                    "criterion": "gastrointestinal resection",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "chronic diarrhea",
                    "criterion": "chronic diarrhea",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "intestinal obstruction",
                    "criterion": "intestinal obstruction",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.",
            "criterions": [
                {
                    "exact_snippets": "uncontrollable pleural effusion",
                    "criterion": "pleural effusion",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrollable"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrollable ... pericardial effusion",
                    "criterion": "pericardial effusion",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrollable"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrollable ... ascites requiring recurrent drainage procedures",
                    "criterion": "ascites",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrollable"
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "recurrent drainage procedures"
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Imaging (CT or MRI) shows that tumor invades large blood vessels or the boundary with blood vessels is unclear.",
            "criterions": [
                {
                    "exact_snippets": "Imaging (CT or MRI) shows that tumor invades large blood vessels",
                    "criterion": "tumor invasion of large blood vessels",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Imaging (CT or MRI) shows that ... the boundary with blood vessels is unclear",
                    "criterion": "unclear boundary with blood vessels",
                    "requirements": [
                        {
                            "requirement_type": "clarity",
                            "expected_value": "unclear"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Has any bleeding or bleeding events ≥ grade 3 or with unhealed wounds, ulcerative , or fractures within 4 weeks prior to the first administration.",
            "criterions": [
                {
                    "exact_snippets": "bleeding or bleeding events ≥ grade 3",
                    "criterion": "bleeding events",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "unhealed wounds",
                    "criterion": "wounds",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "unhealed"
                        }
                    ]
                },
                {
                    "exact_snippets": "ulcerative",
                    "criterion": "ulcerative condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "fractures",
                    "criterion": "fractures",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Has uncontrollable symptoms of brain metastases, spinal cord compression, cancerous meningitis within 8 weeks before the first-dosing, or brain or leptomeningeal disease found by CT or MRI during screening.",
            "criterions": [
                {
                    "exact_snippets": "uncontrollable symptoms of brain metastases",
                    "criterion": "brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "uncontrollable"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrollable symptoms of ... spinal cord compression",
                    "criterion": "spinal cord compression",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "uncontrollable"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrollable symptoms of ... cancerous meningitis",
                    "criterion": "cancerous meningitis",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "uncontrollable"
                        }
                    ]
                },
                {
                    "exact_snippets": "brain or leptomeningeal disease found by CT or MRI during screening",
                    "criterion": "brain disease",
                    "requirements": [
                        {
                            "requirement_type": "detection",
                            "expected_value": [
                                "CT",
                                "MRI"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "brain or leptomeningeal disease found by CT or MRI during screening",
                    "criterion": "leptomeningeal disease",
                    "requirements": [
                        {
                            "requirement_type": "detection",
                            "expected_value": [
                                "CT",
                                "MRI"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Has received chemotherapy, surgery, radiotherapy, the last treatment from the first dose less than 4 weeks, or oral targeted drugs for less than 5 half-lives, or oral fluorouracil pyridine drugs for less than 14 days, mitomycin C and nitrosourea for less than 6 weeks. Patients whose adverse events (except alopecia) caused by previous treatment did not recover to ≤ grade 1.",
            "criterions": [
                {
                    "exact_snippets": "Has received chemotherapy, surgery, radiotherapy",
                    "criterion": "previous treatments",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "the last treatment from the first dose less than 4 weeks",
                    "criterion": "time since last treatment",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "oral targeted drugs for less than 5 half-lives",
                    "criterion": "time since last oral targeted drugs",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<",
                                "value": 5,
                                "unit": "half-lives"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "oral fluorouracil pyridine drugs for less than 14 days",
                    "criterion": "time since last oral fluorouracil pyridine drugs",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "mitomycin C and nitrosourea for less than 6 weeks",
                    "criterion": "time since last mitomycin C and nitrosourea",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<",
                                "value": 6,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients whose adverse events (except alopecia) caused by previous treatment did not recover to ≤ grade 1",
                    "criterion": "recovery from adverse events",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Patients with any serious and/or uncontrollable disease, including :",
            "criterions": [
                {
                    "exact_snippets": "any serious and/or uncontrollable disease",
                    "criterion": "serious and/or uncontrollable disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Has poor blood pressure control, systolic blood pressure ≥ 150 mmHg, diastolic blood pressure ≥ 90 mmHg;",
            "criterions": [
                {
                    "exact_snippets": "poor blood pressure control",
                    "criterion": "blood pressure control",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "poor"
                        }
                    ]
                },
                {
                    "exact_snippets": "systolic blood pressure ≥ 150 mmHg",
                    "criterion": "systolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 150,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "diastolic blood pressure ≥ 90 mmHg",
                    "criterion": "diastolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 90,
                                "unit": "mmHg"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Thrombotic events, ischemic attacks, myocardial infarction, grade 2 congestive heart failure or arrhythmias requiring treatment including QTc ≥ 480ms occurred within 6 months of first administration;",
            "criterions": [
                {
                    "exact_snippets": "Thrombotic events ... occurred within 6 months of first administration",
                    "criterion": "thrombotic events",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months of first administration"
                        }
                    ]
                },
                {
                    "exact_snippets": "ischemic attacks ... occurred within 6 months of first administration",
                    "criterion": "ischemic attacks",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months of first administration"
                        }
                    ]
                },
                {
                    "exact_snippets": "myocardial infarction ... occurred within 6 months of first administration",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months of first administration"
                        }
                    ]
                },
                {
                    "exact_snippets": "grade 2 congestive heart failure ... occurred within 6 months of first administration",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "grade 2"
                        },
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months of first administration"
                        }
                    ]
                },
                {
                    "exact_snippets": "arrhythmias requiring treatment ... occurred within 6 months of first administration",
                    "criterion": "arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "treatment requirement",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months of first administration"
                        }
                    ]
                },
                {
                    "exact_snippets": "QTc ≥ 480ms",
                    "criterion": "QTc interval",
                    "requirements": [
                        {
                            "requirement_type": "length",
                            "expected_value": {
                                "operator": ">=",
                                "value": 480,
                                "unit": "ms"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Severe active or uncontrolled infections ≥ grade 2;",
            "criterions": [
                {
                    "exact_snippets": "Severe active or uncontrolled infections ≥ grade 2",
                    "criterion": "infections",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Has known clinical history of liver diseases, including viral hepatitis, known carriers of hepatitis B virus (HBV) must exclude active HBV infection, that is, HBV DNA positive > 1 *104 copies/mL or > 2000 IU/mL, known hepatitis C virus infection (HCV) and HCV RNA positive > 1 *103 copies/mL, or other decompensated hepatitis and chronic hepatitis, which require antiviral treatment;",
            "criterions": [
                {
                    "exact_snippets": "known clinical history of liver diseases",
                    "criterion": "liver diseases",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "viral hepatitis",
                    "criterion": "viral hepatitis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "known carriers of hepatitis B virus (HBV)",
                    "criterion": "hepatitis B virus (HBV) carrier status",
                    "requirements": [
                        {
                            "requirement_type": "carrier status",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HBV DNA positive > 1 *104 copies/mL or > 2000 IU/mL",
                    "criterion": "active HBV infection",
                    "requirements": [
                        {
                            "requirement_type": "HBV DNA level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">",
                                        "value": 10000,
                                        "unit": "copies/mL"
                                    },
                                    {
                                        "operator": ">",
                                        "value": 2000,
                                        "unit": "IU/mL"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "known hepatitis C virus infection (HCV)",
                    "criterion": "hepatitis C virus (HCV) infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HCV RNA positive > 1 *103 copies/mL",
                    "criterion": "active HCV infection",
                    "requirements": [
                        {
                            "requirement_type": "HCV RNA level",
                            "expected_value": {
                                "operator": ">",
                                "value": 1000,
                                "unit": "copies/mL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "other decompensated hepatitis",
                    "criterion": "decompensated hepatitis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "chronic hepatitis, which require antiviral treatment",
                    "criterion": "chronic hepatitis requiring antiviral treatment",
                    "requirements": [
                        {
                            "requirement_type": "treatment requirement",
                            "expected_value": "antiviral treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. HIV positive;",
            "criterions": [
                {
                    "exact_snippets": "HIV positive",
                    "criterion": "HIV status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Poor control of diabetes mellitus, fasting blood-glucose ≥ grade 2;",
            "criterions": [
                {
                    "exact_snippets": "Poor control of diabetes mellitus",
                    "criterion": "diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "poor"
                        }
                    ]
                },
                {
                    "exact_snippets": "fasting blood-glucose ≥ grade 2",
                    "criterion": "fasting blood-glucose",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Has vaccinated with vaccines or attenuated vaccines within 4 weeks prior to first administration.",
            "criterions": [
                {
                    "exact_snippets": "vaccinated with vaccines or attenuated vaccines within 4 weeks prior to first administration",
                    "criterion": "vaccination",
                    "requirements": [
                        {
                            "requirement_type": "time since vaccination",
                            "expected_value": {
                                "operator": "<=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. According to the judgement of the researchers, there are other factors that may lead to the termination of the study.",
            "criterions": [
                {
                    "exact_snippets": "other factors that may lead to the termination of the study",
                    "criterion": "factors leading to study termination",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [
        {
            "line": "1. Prior therapy with Anlotinib, anti-programmed cell death (PD)-1, anti-PD-L1 or other immunotherapy against PD-1/PD-L1.",
            "criterions": [
                {
                    "exact_snippets": "Prior therapy with Anlotinib",
                    "criterion": "prior therapy with Anlotinib",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "prior therapy with ... anti-programmed cell death (PD)-1",
                    "criterion": "prior therapy with anti-PD-1",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "prior therapy with ... anti-PD-L1",
                    "criterion": "prior therapy with anti-PD-L1",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "prior therapy with ... other immunotherapy against PD-1/PD-L1",
                    "criterion": "prior therapy with other immunotherapy against PD-1/PD-L1",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "failed_miscellaneous": []
}