{
    "info": {
        "nct_id": "NCT05291182",
        "official_title": "A First-in-human, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of SY-4835 Tablets in Patients With Advanced Solid Tumor",
        "inclusion_criteria": "* For inclusion in this study, patients must fulfil the following criteria:\n\n  1. Must understand andvoluntarily sign the informed consent form, willing to follow and able to complete all study procedures.\n  2. Male or female (age of 18~75 years old ).\n  3. Eastern Collaboration Oncology Group (ECOG) performance status (PS) scored of 0-1.\n  4. Estimated life expectancy ≥3 months.\n  5. Histological or cytological confirmation of a advanced solid tumor, that failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.\n  6. At least 1 measureable lesion for solid tumors assessed using RECIST 1.1.\n  7. Patients must have adequate organ function as defined below (no supportive treatment for the following parameters within 7 days prior to testing):\n\n     Liver function:\n\n     Patients without hepatic metastasis, aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 times institutional upper limit of normal (ULN), total bilirubin (TBIL) ≤ 1.5 times ULN; Patients with hepatic metastasis, AST, ALT ≤ 5 times ULN, TBIL ≤ 1.5 times ULN; Patients with hepatoma carcinoma, AST and ALT ≤ 5 times ULN, TBIL ≤ 2.5 times ULN.\n\n     Bone marrow function:\n\n     Absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelets (PLT) count ≥ 75×10^9/L; Hemoglobin (HB) ≥ 80 g/L.\n\n     Renal function:\n\n     Creatinine clearance ≥ 45 mL/min or serum creatinine ≤ 1.5 times ULN.\n\n     Coagulation function:\n\n     Activated partial thromboplastin time (APTT) ≤ 1.5×ULN; International Normalized ratio (INR) ≤ 1.5×ULN.\n  8. Women of childbearing age performed a serum pregnancy test within 7 days before the initiation of treatment, and agreed to adopt a reliable and effective contraceptive method during the trial and within 90 days after the final administration of the study drug.\nHealthy volunteers allowed\nMust have minimum age of 18 Years\nMust have maximum age of 75 Years",
        "exclusion_criteria": "* Patients must not enrol in this study if any of the following exclusion criteria are fulfilled:\n\n  1. Have received chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy and other anti-tumor therapy within 3 weeks prior to the first use of the study drug, except for the following:\n\n     Nitrosourea or mitomycin C were used within 6 weeks prior to the first use of the study drug; Oral fluorouracil and small molecule targeted drugs were used within 2 weeks or within 5 half-lives prior to the first use of the study; Chinese medicines were used within 2 weeks prior to the first use of the study drug.\n  2. Have received an unmarketed clinical investigational drug or treatment within 4 weeks prior to the first use of the study drug.\n  3. Had major organ surgery (excluding needle biopsy) or had significant traumatism within 4 weeks prior to the first use of study drug.\n  4. History of any WEE1 inhibitor treatment.\n  5. With the exception of alopecia and ≤ Grade 2 peripheral neuropathy, any unresolved toxicities from prior treatment ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) at the time of starting study treatment.\n  6. Evidence of central nervous system (CNS) metastases accompanied with clinical symptoms, or other evidence of uncontrolled CNS metastases judged by investigators that the patient should not participate in the study.\n  7. Patients have serous effusion (such as pleural effusion, peritoneal effusion, pericardial effusion, etc.) with clinical symptoms, effusions will still increase after 2 weeks of conservative treatment (excluding drainage).\n  8. Patients with active uncontrolled systemic bacterial, viral, or fungal infection despite optimal treatment.\n  9. Active hepatitis B (HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL), Hepatitis C virus infection (HCVAb-positive and HCV-RNA ≥ 1000 IU/ml); Human immunodeficiency virus antibody (HIV Ab) positive; Active syphilis.\n  10. Have serious cardiovascular and cerebrovascular diseases, including but not limited to:\n\n      Severe arrhythmias or abnormal cardiac conduction, such as ventricular arrhythmias requiring clinical intervention, degree ii-iii atrioventricular block, etc; Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs); Had acute coronary syndrome, congestive heart failure, aortic dissection, or other grade 3 or higher cardio-cerebrovascular events within 6 months prior to the first use of study drug; Heart failure (New York Heart Association, NYHA) class ≥ II or left ventricular ejection fraction (LVEF) < 40 %; Hypertension remains uncontrolled after aggressive antihypertensive therapy. Uncontrolled hypertension was defined as systolic blood pressure > 185 mmHg and/or diastolic blood pressure > 110 mmHg measured on 3 repetitions at least 10 minutes apart.\n  11. Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4 and CYP2D6 within 7 days prior to the first dose of study treatment.\n  12. Patients with alcohol and/or drug dependence.\n  13. Women who are breastfeeding.\n  14. Patients suffering from conditions which are likely to adversely affect gastrointestinal motility.\n  15. Patients with malignancies other than tumors treated in this study (except: malignancies that are cured and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancer; completely resected carcinoma in situ of any type).\n  16. The investigator considers that the subject has a history of other serious systemic diseases or other reasons and is not suitable to participate in this clinical study.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "2. Male or female (age of 18~75 years old ).",
            "criterions": [
                {
                    "exact_snippets": "Male or female",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "age of 18~75 years old",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "range",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 18,
                                        "unit": "years"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 75,
                                        "unit": "years"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Eastern Collaboration Oncology Group (ECOG) performance status (PS) scored of 0-1.",
            "criterions": [
                {
                    "exact_snippets": "Eastern Collaboration Oncology Group (ECOG) performance status (PS) scored of 0-1.",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "score",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 0,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 1,
                                        "unit": "N/A"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Estimated life expectancy ≥3 months.",
            "criterions": [
                {
                    "exact_snippets": "Estimated life expectancy ≥3 months.",
                    "criterion": "life expectancy",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Histological or cytological confirmation of a advanced solid tumor, that failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.",
            "criterions": [
                {
                    "exact_snippets": "Histological or cytological confirmation of a advanced solid tumor",
                    "criterion": "advanced solid tumor",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": [
                                "histological",
                                "cytological"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "failed to respond to standard therapy",
                    "criterion": "response to standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "response",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "progressed despite standard therapy",
                    "criterion": "progression despite standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "progression",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "for which standard therapy does not exist",
                    "criterion": "availability of standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "existence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. At least 1 measureable lesion for solid tumors assessed using RECIST 1.1.",
            "criterions": [
                {
                    "exact_snippets": "At least 1 measureable lesion for solid tumors",
                    "criterion": "measurable lesion",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Patients must have adequate organ function as defined below (no supportive treatment for the following parameters within 7 days prior to testing):",
            "criterions": [
                {
                    "exact_snippets": "adequate organ function",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "no supportive treatment ... within 7 days prior to testing",
                    "criterion": "supportive treatment",
                    "requirements": [
                        {
                            "requirement_type": "absence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 7,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Liver function:",
            "criterions": [
                {
                    "exact_snippets": "Liver function",
                    "criterion": "liver function",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": "N/A"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Bone marrow function:",
            "criterions": [
                {
                    "exact_snippets": "Bone marrow function",
                    "criterion": "bone marrow function",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": "N/A"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelets (PLT) count ≥ 75×10^9/L; Hemoglobin (HB) ≥ 80 g/L.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) ≥ 1.5×10^9/L",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "×10^9/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Platelets (PLT) count ≥ 75×10^9/L",
                    "criterion": "platelets count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 75,
                                "unit": "×10^9/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Hemoglobin (HB) ≥ 80 g/L",
                    "criterion": "hemoglobin",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 80,
                                "unit": "g/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Renal function:",
            "criterions": [
                {
                    "exact_snippets": "Renal function:",
                    "criterion": "renal function",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": "N/A"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Creatinine clearance ≥ 45 mL/min or serum creatinine ≤ 1.5 times ULN.",
            "criterions": [
                {
                    "exact_snippets": "Creatinine clearance ≥ 45 mL/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 45,
                                "unit": "mL/min"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "serum creatinine ≤ 1.5 times ULN",
                    "criterion": "serum creatinine",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "times ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Coagulation function:",
            "criterions": [
                {
                    "exact_snippets": "Coagulation function:",
                    "criterion": "coagulation function",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": "N/A"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Activated partial thromboplastin time (APTT) ≤ 1.5×ULN; International Normalized ratio (INR) ≤ 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"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Women of childbearing age performed a serum pregnancy test within 7 days before the initiation of treatment, and agreed to adopt a reliable and effective contraceptive method during the trial and within 90 days after the final administration of the study drug.",
            "criterions": [
                {
                    "exact_snippets": "Women of childbearing age",
                    "criterion": "gender and reproductive status",
                    "requirements": [
                        {
                            "requirement_type": "gender",
                            "expected_value": "female"
                        },
                        {
                            "requirement_type": "reproductive status",
                            "expected_value": "childbearing age"
                        }
                    ]
                },
                {
                    "exact_snippets": "performed a serum pregnancy test within 7 days before the initiation of treatment",
                    "criterion": "serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 7 days before the initiation of treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "agreed to adopt a reliable and effective contraceptive method during the trial and within 90 days after the final administration of the study drug",
                    "criterion": "contraceptive method",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": "during the trial and within 90 days after the final administration of the study drug"
                        }
                    ]
                }
            ]
        },
        {
            "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"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have maximum age of 75 Years",
            "criterions": [
                {
                    "exact_snippets": "maximum age of 75 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "maximum",
                            "expected_value": {
                                "operator": "<=",
                                "value": 75,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "1. Have received chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy and other anti-tumor therapy within 3 weeks prior to the first use of the study drug, except for the following:",
            "criterions": [
                {
                    "exact_snippets": "Have received chemotherapy ... within 3 weeks prior to the first use of the study drug",
                    "criterion": "chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Have received ... radiotherapy ... within 3 weeks prior to the first use of the study drug",
                    "criterion": "radiotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Have received ... biotherapy ... within 3 weeks prior to the first use of the study drug",
                    "criterion": "biotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Have received ... endocrine therapy ... within 3 weeks prior to the first use of the study drug",
                    "criterion": "endocrine therapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Have received ... immunotherapy ... within 3 weeks prior to the first use of the study drug",
                    "criterion": "immunotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Have received ... other anti-tumor therapy within 3 weeks prior to the first use of the study drug",
                    "criterion": "other anti-tumor therapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Nitrosourea or mitomycin C were used within 6 weeks prior to the first use of the study drug; Oral fluorouracil and small molecule targeted drugs were used within 2 weeks or within 5 half-lives prior to the first use of the study; Chinese medicines were used within 2 weeks prior to the first use of the study drug.",
            "criterions": [
                {
                    "exact_snippets": "Nitrosourea or mitomycin C were used within 6 weeks prior to the first use of the study drug",
                    "criterion": "use of nitrosourea or mitomycin C",
                    "requirements": [
                        {
                            "requirement_type": "time since last use",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 6,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Oral fluorouracil and small molecule targeted drugs were used within 2 weeks or within 5 half-lives prior to the first use of the study",
                    "criterion": "use of oral fluorouracil and small molecule targeted drugs",
                    "requirements": [
                        {
                            "requirement_type": "time since last use",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        },
                        {
                            "requirement_type": "time since last use",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "half-lives"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Chinese medicines were used within 2 weeks prior to the first use of the study drug",
                    "criterion": "use of Chinese medicines",
                    "requirements": [
                        {
                            "requirement_type": "time since last use",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Have received an unmarketed clinical investigational drug or treatment within 4 weeks prior to the first use of the study drug.",
            "criterions": [
                {
                    "exact_snippets": "Have received an unmarketed clinical investigational drug or treatment within 4 weeks prior to the first use of the study drug.",
                    "criterion": "unmarketed clinical investigational drug or treatment",
                    "requirements": [
                        {
                            "requirement_type": "time since last administration",
                            "expected_value": {
                                "operator": "<=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Had major organ surgery (excluding needle biopsy) or had significant traumatism within 4 weeks prior to the first use of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Had major organ surgery (excluding needle biopsy) ... within 4 weeks prior to the first use of study drug.",
                    "criterion": "major organ surgery",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 4,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "had significant traumatism within 4 weeks prior to the first use of study drug.",
                    "criterion": "significant traumatism",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 4,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. History of any WEE1 inhibitor treatment.",
            "criterions": [
                {
                    "exact_snippets": "History of any WEE1 inhibitor treatment",
                    "criterion": "WEE1 inhibitor treatment",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. With the exception of alopecia and ≤ Grade 2 peripheral neuropathy, any unresolved toxicities from prior treatment ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) at the time of starting study treatment.",
            "criterions": [
                {
                    "exact_snippets": "alopecia",
                    "criterion": "alopecia",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "≤ Grade 2 peripheral neuropathy",
                    "criterion": "peripheral neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "Grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "any unresolved toxicities from prior treatment ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE)",
                    "criterion": "unresolved toxicities from prior treatment",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "Grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Evidence of central nervous system (CNS) metastases accompanied with clinical symptoms, or other evidence of uncontrolled CNS metastases judged by investigators that the patient should not participate in the study.",
            "criterions": [
                {
                    "exact_snippets": "Evidence of central nervous system (CNS) metastases",
                    "criterion": "central nervous system (CNS) metastases",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "accompanied with clinical symptoms",
                    "criterion": "clinical symptoms of CNS metastases",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "other evidence of uncontrolled CNS metastases",
                    "criterion": "uncontrolled CNS metastases",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Patients have serous effusion (such as pleural effusion, peritoneal effusion, pericardial effusion, etc.) with clinical symptoms, effusions will still increase after 2 weeks of conservative treatment (excluding drainage).",
            "criterions": [
                {
                    "exact_snippets": "Patients have serous effusion (such as pleural effusion, peritoneal effusion, pericardial effusion, etc.)",
                    "criterion": "serous effusion",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "with clinical symptoms",
                    "criterion": "clinical symptoms of serous effusion",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "effusions will still increase after 2 weeks of conservative treatment (excluding drainage)",
                    "criterion": "effusion increase after conservative treatment",
                    "requirements": [
                        {
                            "requirement_type": "persistence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Patients with active uncontrolled systemic bacterial, viral, or fungal infection despite optimal treatment.",
            "criterions": [
                {
                    "exact_snippets": "active uncontrolled systemic bacterial, viral, or fungal infection",
                    "criterion": "systemic infection",
                    "requirements": [
                        {
                            "requirement_type": "control status",
                            "expected_value": "uncontrolled"
                        },
                        {
                            "requirement_type": "activity status",
                            "expected_value": "active"
                        }
                    ]
                },
                {
                    "exact_snippets": "despite optimal treatment",
                    "criterion": "treatment status",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": "optimal treatment not effective"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Active hepatitis B (HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL), Hepatitis C virus infection (HCVAb-positive and HCV-RNA ≥ 1000 IU/ml); Human immunodeficiency virus antibody (HIV Ab) positive; Active syphilis.",
            "criterions": [
                {
                    "exact_snippets": "Active hepatitis B (HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL)",
                    "criterion": "hepatitis B",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "HBsAg",
                            "expected_value": "positive"
                        },
                        {
                            "requirement_type": "HBV-DNA",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2000,
                                "unit": "IU/mL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Hepatitis C virus infection (HCVAb-positive and HCV-RNA ≥ 1000 IU/ml)",
                    "criterion": "hepatitis C virus infection",
                    "requirements": [
                        {
                            "requirement_type": "HCVAb",
                            "expected_value": "positive"
                        },
                        {
                            "requirement_type": "HCV-RNA",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1000,
                                "unit": "IU/ml"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Human immunodeficiency virus antibody (HIV Ab) positive",
                    "criterion": "HIV antibody",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "Active syphilis",
                    "criterion": "syphilis",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Have serious cardiovascular and cerebrovascular diseases, including but not limited to:",
            "criterions": [
                {
                    "exact_snippets": "serious cardiovascular and cerebrovascular diseases",
                    "criterion": "cardiovascular and cerebrovascular diseases",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "serious"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Severe arrhythmias or abnormal cardiac conduction, such as ventricular arrhythmias requiring clinical intervention, degree ii-iii atrioventricular block, etc; Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs); Had acute coronary syndrome, congestive heart failure, aortic dissection, or other grade 3 or higher cardio-cerebrovascular events within 6 months prior to the first use of study drug; Heart failure (New York Heart Association, NYHA) class ≥ II or left ventricular ejection fraction (LVEF) < 40 %; Hypertension remains uncontrolled after aggressive antihypertensive therapy. Uncontrolled hypertension was defined as systolic blood pressure > 185 mmHg and/or diastolic blood pressure > 110 mmHg measured on 3 repetitions at least 10 minutes apart.",
            "criterions": [
                {
                    "exact_snippets": "Severe arrhythmias or abnormal cardiac conduction, such as ventricular arrhythmias requiring clinical intervention",
                    "criterion": "arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "ventricular arrhythmias requiring clinical intervention"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "degree ii-iii atrioventricular block",
                    "criterion": "atrioventricular block",
                    "requirements": [
                        {
                            "requirement_type": "degree",
                            "expected_value": "ii-iii"
                        }
                    ]
                },
                {
                    "exact_snippets": "Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs)",
                    "criterion": "QT interval",
                    "requirements": [
                        {
                            "requirement_type": "mean corrected QT interval",
                            "expected_value": {
                                "operator": ">",
                                "value": 470,
                                "unit": "msec"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Had acute coronary syndrome, congestive heart failure, aortic dissection, or other grade 3 or higher cardio-cerebrovascular events within 6 months prior to the first use of study drug",
                    "criterion": "cardio-cerebrovascular events",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "acute coronary syndrome",
                                "congestive heart failure",
                                "aortic dissection",
                                "other grade 3 or higher events"
                            ]
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within 6 months prior to the first use of study drug"
                        }
                    ]
                },
                {
                    "exact_snippets": "Heart failure (New York Heart Association, NYHA) class ≥ II",
                    "criterion": "heart failure class",
                    "requirements": [
                        {
                            "requirement_type": "classification",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "NYHA class"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "left ventricular ejection fraction (LVEF) < 40 %",
                    "criterion": "left ventricular ejection fraction",
                    "requirements": [
                        {
                            "requirement_type": "percentage",
                            "expected_value": {
                                "operator": "<",
                                "value": 40,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Hypertension remains uncontrolled after aggressive antihypertensive therapy",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control status",
                            "expected_value": "uncontrolled after aggressive antihypertensive therapy"
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled hypertension was defined as systolic blood pressure > 185 mmHg and/or diastolic blood pressure > 110 mmHg measured on 3 repetitions at least 10 minutes apart",
                    "criterion": "blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "systolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 185,
                                "unit": "mmHg"
                            }
                        },
                        {
                            "requirement_type": "diastolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 110,
                                "unit": "mmHg"
                            }
                        },
                        {
                            "requirement_type": "measurement conditions",
                            "expected_value": "measured on 3 repetitions at least 10 minutes apart"
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4 and CYP2D6 within 7 days prior to the first dose of study treatment.",
            "criterions": [
                {
                    "exact_snippets": "Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4",
                    "criterion": "use of CYP3A4 inhibitors/inducers",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of ... CYP2D6",
                    "criterion": "use of CYP2D6 inhibitors/inducers",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "within 7 days prior to the first dose of study treatment",
                    "criterion": "timeframe for drug use",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 7 days prior to the first dose of study treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Patients with alcohol and/or drug dependence.",
            "criterions": [
                {
                    "exact_snippets": "Patients with alcohol ... dependence.",
                    "criterion": "alcohol dependence",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with ... drug dependence.",
                    "criterion": "drug dependence",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Women who are breastfeeding.",
            "criterions": [
                {
                    "exact_snippets": "Women who are breastfeeding",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Patients suffering from conditions which are likely to adversely affect gastrointestinal motility.",
            "criterions": [
                {
                    "exact_snippets": "conditions which are likely to adversely affect gastrointestinal motility",
                    "criterion": "gastrointestinal motility",
                    "requirements": [
                        {
                            "requirement_type": "adverse effect",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "15. Patients with malignancies other than tumors treated in this study (except: malignancies that are cured and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancer; completely resected carcinoma in situ of any type).",
            "criterions": [
                {
                    "exact_snippets": "Patients with malignancies other than tumors treated in this study",
                    "criterion": "malignancies other than tumors treated in this study",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "malignancies that are cured and have not recurred within 3 years prior to study entry",
                    "criterion": "malignancies",
                    "requirements": [
                        {
                            "requirement_type": "cured",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "recurrence",
                            "expected_value": {
                                "operator": "<",
                                "value": 3,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "completely resected basal cell and squamous cell skin cancer",
                    "criterion": "basal cell and squamous cell skin cancer",
                    "requirements": [
                        {
                            "requirement_type": "resection",
                            "expected_value": "complete"
                        }
                    ]
                },
                {
                    "exact_snippets": "completely resected carcinoma in situ of any type",
                    "criterion": "carcinoma in situ",
                    "requirements": [
                        {
                            "requirement_type": "resection",
                            "expected_value": "complete"
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. The investigator considers that the subject has a history of other serious systemic diseases or other reasons and is not suitable to participate in this clinical study.",
            "criterions": [
                {
                    "exact_snippets": "history of other serious systemic diseases",
                    "criterion": "serious systemic diseases",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "other reasons and is not suitable to participate",
                    "criterion": "suitability to participate",
                    "requirements": [
                        {
                            "requirement_type": "suitability",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [
        {
            "line": "* For inclusion in this study, patients must fulfil the following criteria:",
            "criterions": []
        },
        {
            "line": "1. Must understand andvoluntarily sign the informed consent form, willing to follow and able to complete all study procedures.",
            "criterions": [
                {
                    "exact_snippets": "Must understand and voluntarily sign the informed consent form",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "understanding",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "signature",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "willing to follow and able to complete all study procedures",
                    "criterion": "study procedures",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "Patients without hepatic metastasis, aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 times institutional upper limit of normal (ULN), total bilirubin (TBIL) ≤ 1.5 times ULN; Patients with hepatic metastasis, AST, ALT ≤ 5 times ULN, TBIL ≤ 1.5 times ULN; Patients with hepatoma carcinoma, AST and ALT ≤ 5 times ULN, TBIL ≤ 2.5 times ULN.",
            "criterions": [
                {
                    "exact_snippets": "Patients without hepatic metastasis",
                    "criterion": "hepatic metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "AST and ALT ≤ 3 times institutional upper limit of normal (ULN)",
                    "criterion": "AST and ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 3,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "total bilirubin (TBIL) ≤ 1.5 times ULN",
                    "criterion": "total bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 1.5,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with hepatic metastasis",
                    "criterion": "hepatic metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "AST, ALT ≤ 5 times ULN",
                    "criterion": "AST and ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "TBIL ≤ 1.5 times ULN",
                    "criterion": "total bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 1.5,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with hepatoma carcinoma",
                    "criterion": "hepatoma carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "AST and ALT ≤ 5 times ULN",
                    "criterion": "AST and ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "TBIL ≤ 2.5 times ULN",
                    "criterion": "total bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "times ULN"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "failed_exclusion": [
        {
            "line": "* Patients must not enrol in this study if any of the following exclusion criteria are fulfilled:",
            "criterions": []
        }
    ],
    "failed_miscellaneous": []
}