{
    "info": {
        "nct_id": "NCT02699073",
        "official_title": "Evaluation of Treatment Response With CHOI and RECIST Criteria and CT Texture Analysis in Patients With Metastatic Colorectal Cancer Treated With Regorafenib. A GERCOR Phase II Study",
        "inclusion_criteria": "1. Signed and dated informed consent.\n2. Patients with histologically proven metastatic colorectal cancer\n3. Patients previously treated with, or who are not considered candidates for available therapies, i.e., fluoropyrimidine-based chemotherapy, anti-VEGF therapy and anti-EGFR therapy (if patients were RAS wild-type).\n4. ECOG PS = 0 or 1\n5. Aged 18-years or older\n6. Life expectancy of at least 3 months\n7. Adequate renal, bone marrow, liver and pancreatic functions:\n\n   * Estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation\n   * Platelet count ≥ 100.000/mm3; hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1500/mm3. Transfusion to meet the inclusion criteria will not be allowed\n   * Total bilirubin ≤ 1.5 the upper limit of normal value (ULN); alanine aminotransferase (ALAT) and aspartame aminotransferase (ASAT) ≤ 3.0 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer and/or have bone metastases)\n8. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluation will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care\n9. At least one target lesion on CT scan\n10. No contraindication to Iodine contrast media injection during CT.\n11. For women of childbearing potential, blood or urine pregnancy test performed a maximum of 7 days before start of study treatment and negative result documented before start of study treatment\n12. When applicable, i.e., women of childbearing potential having sexual activity, men having sexual activity, must agree to use an adequate contraception before entering the study, until at least 8 weeks after the last study drug administration\n13. Registration in a national health care system (CMU included).\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "1. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial ; planned surgical procedure within the first month of treatment or any procedure that might change the timing of regorafenib administration during the first month of treatment\n2. Patients under judicial protection (curatorship, tutorship) and/or deprived of freedom\n3. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication\n4. Pregnancy or breastfeeding\n5. Congestive heart failure ≥ New York Heart Association (NYHA) class 2\n6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)\n7. Myocardial infarction less than 6 months before the start of study medication\n8. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted)\n9. Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management)\n10. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication\n11. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2, NCI-CTCAE v 4.0 dyspnea)\n12. Ongoing infection >grade 2, NCI- CTCAE v 4.0\n13. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])\n14. Known history of human immunodeficiency virus (HIV) infection\n15. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy\n16. Patients with seizure disorder requiring medication\n17. History of organ allograft\n18. Patients with evidence or history of any bleeding diathesis, irrespective of severity\n19. Any hemorrhage or bleeding event ≥ Grade 3, NCI-CTCAE v 4.0 within 4 weeks prior to the start of study medication\n20. Non-healing wound, non-healing ulcer or non-healing bone fracture\n21. Dehydration grade ≥1, NCI-CTCAE v 4.0\n22. Known hypersensitivity to the study drug, study drug classes or excipient in the formulation\n23. Interstitial lung disease with ongoing signs or symptoms at the time of inclusion\n24. Persistent proteinuria >3.5 g/24 hour measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCI-CTCAE v 4.0)\n25. Patients unable to swallow oral medication\n26. Any malabsorption condition\n27. Unresolved toxicity higher than Grade 1, NCI-CTCAE v 4.0, attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neuropathy\n28. Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks\n29. Treatment with any other investigational medicinal product within 28 days prior to study entry\n30. Chronic treatment potentially interacting with the study medication, i.e. strong CYP3A4 inducers/inhibitors, strong UGT1A9 inhibitors",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "1. Signed and dated informed consent.",
            "criterions": [
                {
                    "exact_snippets": "Signed and dated informed consent.",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "signed",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "dated",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Patients with histologically proven metastatic colorectal cancer",
            "criterions": [
                {
                    "exact_snippets": "histologically proven metastatic colorectal cancer",
                    "criterion": "metastatic colorectal cancer",
                    "requirements": [
                        {
                            "requirement_type": "confirmation method",
                            "expected_value": "histologically proven"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Patients previously treated with, or who are not considered candidates for available therapies, i.e., fluoropyrimidine-based chemotherapy, anti-VEGF therapy and anti-EGFR therapy (if patients were RAS wild-type).",
            "criterions": [
                {
                    "exact_snippets": "Patients previously treated with ... fluoropyrimidine-based chemotherapy",
                    "criterion": "previous treatment with fluoropyrimidine-based chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients ... who are not considered candidates for ... fluoropyrimidine-based chemotherapy",
                    "criterion": "candidate for fluoropyrimidine-based chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients previously treated with ... anti-VEGF therapy",
                    "criterion": "previous treatment with anti-VEGF therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients ... who are not considered candidates for ... anti-VEGF therapy",
                    "criterion": "candidate for anti-VEGF therapy",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients previously treated with ... anti-EGFR therapy",
                    "criterion": "previous treatment with anti-EGFR therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients ... who are not considered candidates for ... anti-EGFR therapy",
                    "criterion": "candidate for anti-EGFR therapy",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "if patients were RAS wild-type",
                    "criterion": "RAS wild-type status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "wild-type"
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. ECOG PS = 0 or 1",
            "criterions": [
                {
                    "exact_snippets": "ECOG PS = 0 or 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Aged 18-years or older",
            "criterions": [
                {
                    "exact_snippets": "Aged 18-years or older",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Life expectancy of at least 3 months",
            "criterions": [
                {
                    "exact_snippets": "Life expectancy of at least 3 months",
                    "criterion": "life expectancy",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Adequate renal, bone marrow, liver and pancreatic functions:",
            "criterions": [
                {
                    "exact_snippets": "Adequate renal ... functions",
                    "criterion": "renal function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Adequate ... bone marrow ... functions",
                    "criterion": "bone marrow function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Adequate ... liver ... functions",
                    "criterion": "liver function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Adequate ... pancreatic functions",
                    "criterion": "pancreatic function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation",
            "criterions": [
                {
                    "exact_snippets": "Estimated creatinine clearance ≥ 30 mL/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 30,
                                "unit": "mL/min"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelet count ≥ 100.000/mm3; hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1500/mm3. Transfusion to meet the inclusion criteria will not be allowed",
            "criterions": [
                {
                    "exact_snippets": "Platelet count ≥ 100.000/mm3",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 100000,
                                "unit": "mm3"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "hemoglobin ≥ 9 g/dL",
                    "criterion": "hemoglobin",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "absolute neutrophil count ≥ 1500/mm3",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mm3"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Total bilirubin ≤ 1.5 the upper limit of normal value (ULN); alanine aminotransferase (ALAT) and aspartame aminotransferase (ASAT) ≤ 3.0 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer and/or have bone metastases)",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin ≤ 1.5 the upper limit of normal value (ULN)",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alanine aminotransferase (ALAT) ... ≤ 3.0 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer)",
                    "criterion": "alanine aminotransferase (ALAT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 3.0,
                                        "unit": "ULN"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 5.0,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "aspartame aminotransferase (ASAT) ... ≤ 3.0 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer)",
                    "criterion": "aspartame aminotransferase (ASAT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 3.0,
                                        "unit": "ULN"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 5.0,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement of their cancer and/or have bone metastases)",
                    "criterion": "alkaline phosphatase (ALP)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "ULN"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 5.0,
                                        "unit": "ULN"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluation will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care",
            "criterions": [
                {
                    "exact_snippets": "International normalized ratio (INR) ≤ 1.5 x ULN",
                    "criterion": "International normalized ratio (INR)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN",
                    "criterion": "partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "unless receiving treatment with therapeutic anticoagulation",
                    "criterion": "treatment with therapeutic anticoagulation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients being treated with anticoagulant, e.g., heparin, will be allowed to participate",
                    "criterion": "treatment with anticoagulant",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "provided no prior evidence of an underlying abnormality in these parameters exists",
                    "criterion": "underlying abnormality in INR and PTT/aPTT",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Close monitoring of at least weekly evaluation will be performed until INR and PTT are stable",
                    "criterion": "monitoring frequency",
                    "requirements": [
                        {
                            "requirement_type": "frequency",
                            "expected_value": "at least weekly"
                        }
                    ]
                },
                {
                    "exact_snippets": "until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care",
                    "criterion": "stability of INR and PTT",
                    "requirements": [
                        {
                            "requirement_type": "stability",
                            "expected_value": "based on a pre-dose measurement as defined by the local standard of care"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. At least one target lesion on CT scan",
            "criterions": [
                {
                    "exact_snippets": "At least one target lesion on CT scan",
                    "criterion": "target lesion",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. No contraindication to Iodine contrast media injection during CT.",
            "criterions": [
                {
                    "exact_snippets": "No contraindication to Iodine contrast media injection during CT.",
                    "criterion": "contraindication to Iodine contrast media injection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. For women of childbearing potential, blood or urine pregnancy test performed a maximum of 7 days before start of study treatment and negative result documented before start of study treatment",
            "criterions": [
                {
                    "exact_snippets": "women of childbearing potential",
                    "criterion": "gender and reproductive status",
                    "requirements": [
                        {
                            "requirement_type": "expected_value",
                            "expected_value": "women of childbearing potential"
                        }
                    ]
                },
                {
                    "exact_snippets": "blood or urine pregnancy test",
                    "criterion": "pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "blood",
                                "urine"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "performed a maximum of 7 days before start of study treatment",
                    "criterion": "timing of pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "operator": "<=",
                                "value": 7,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "negative result documented before start of study treatment",
                    "criterion": "pregnancy test result",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. When applicable, i.e., women of childbearing potential having sexual activity, men having sexual activity, must agree to use an adequate contraception before entering the study, until at least 8 weeks after the last study drug administration",
            "criterions": [
                {
                    "exact_snippets": "women of childbearing potential",
                    "criterion": "women of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "sexual activity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "men having sexual activity",
                    "criterion": "men having sexual activity",
                    "requirements": [
                        {
                            "requirement_type": "sexual activity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "must agree to use an adequate contraception",
                    "criterion": "contraception use",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "until at least 8 weeks after the last study drug administration",
                    "criterion": "contraception duration",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 8,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Registration in a national health care system (CMU included).",
            "criterions": [
                {
                    "exact_snippets": "Registration in a national health care system (CMU included)",
                    "criterion": "national health care system registration",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "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": "1. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial ; planned surgical procedure within the first month of treatment or any procedure that might change the timing of regorafenib administration during the first month of treatment",
            "criterions": [
                {
                    "exact_snippets": "psychological, familial, sociological or geographical condition potentially hampering compliance",
                    "criterion": "condition hampering compliance",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "planned surgical procedure within the first month of treatment",
                    "criterion": "planned surgical procedure",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "month"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "any procedure that might change the timing of regorafenib administration during the first month of treatment",
                    "criterion": "procedure affecting regorafenib administration",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "month"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Patients under judicial protection (curatorship, tutorship) and/or deprived of freedom",
            "criterions": [
                {
                    "exact_snippets": "Patients under judicial protection (curatorship, tutorship)",
                    "criterion": "judicial protection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "deprived of freedom",
                    "criterion": "freedom deprivation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication",
            "criterions": [
                {
                    "exact_snippets": "Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication",
                    "criterion": "major surgical procedure",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication",
                    "criterion": "open biopsy",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication",
                    "criterion": "significant traumatic injury",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Pregnancy or breastfeeding",
            "criterions": [
                {
                    "exact_snippets": "Pregnancy",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "breastfeeding",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Congestive heart failure ≥ New York Heart Association (NYHA) class 2",
            "criterions": [
                {
                    "exact_snippets": "Congestive heart failure ≥ New York Heart Association (NYHA) class 2",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "NYHA class"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)",
            "criterions": [
                {
                    "exact_snippets": "Unstable angina (angina symptoms at rest)",
                    "criterion": "unstable angina",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "new-onset angina (begun within the last 3 months)",
                    "criterion": "new-onset angina",
                    "requirements": [
                        {
                            "requirement_type": "onset time",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Myocardial infarction less than 6 months before the start of study medication",
            "criterions": [
                {
                    "exact_snippets": "Myocardial infarction less than 6 months before the start of study medication",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "operator": "<",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted)",
            "criterions": [
                {
                    "exact_snippets": "Cardiac arrhythmias requiring anti-arrhythmic therapy",
                    "criterion": "cardiac arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "requiring anti-arrhythmic therapy"
                        }
                    ]
                },
                {
                    "exact_snippets": "beta-blockers or digoxin are permitted",
                    "criterion": "anti-arrhythmic therapy",
                    "requirements": [
                        {
                            "requirement_type": "permitted medications",
                            "expected_value": [
                                "beta-blockers",
                                "digoxin"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management)",
            "criterions": [
                {
                    "exact_snippets": "Uncontrolled hypertension",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "systolic blood pressure >140 mmHg",
                    "criterion": "systolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 140,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "diastolic pressure >90 mmHg",
                    "criterion": "diastolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 90,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "despite optimal medical management",
                    "criterion": "medical management",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": "optimal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication",
            "criterions": [
                {
                    "exact_snippets": "Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication",
                    "criterion": "thrombotic or embolic events",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication",
                    "criterion": "catheter-related venous thrombosis",
                    "requirements": [
                        {
                            "requirement_type": "treatment adequacy",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "operator": ">",
                                "value": 1,
                                "unit": "month"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2, NCI-CTCAE v 4.0 dyspnea)",
            "criterions": [
                {
                    "exact_snippets": "Pleural effusion",
                    "criterion": "pleural effusion",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": ">= CTCAE grade 2"
                        }
                    ]
                },
                {
                    "exact_snippets": "ascites",
                    "criterion": "ascites",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": ">= CTCAE grade 2"
                        }
                    ]
                },
                {
                    "exact_snippets": "respiratory compromise (≥ CTCAE grade 2, NCI-CTCAE v 4.0 dyspnea)",
                    "criterion": "respiratory compromise",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": ">= CTCAE grade 2"
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Ongoing infection >grade 2, NCI- CTCAE v 4.0",
            "criterions": [
                {
                    "exact_snippets": "Ongoing infection >grade 2, NCI- CTCAE v 4.0",
                    "criterion": "ongoing infection",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 2,
                                "unit": "grade (NCI-CTCAE v 4.0)"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])",
            "criterions": [
                {
                    "exact_snippets": "Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion",
                    "criterion": "previous or concurrent cancer",
                    "requirements": [
                        {
                            "requirement_type": "distinctness",
                            "expected_value": "distinct in primary site or histology from colorectal cancer"
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "except for curatively treated cervical cancer in situ",
                    "criterion": "cervical cancer in situ",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "curatively treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... non-melanoma skin cancer",
                    "criterion": "non-melanoma skin cancer",
                    "requirements": [
                        {
                            "requirement_type": "exclusion",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])",
                    "criterion": "superficial bladder tumors",
                    "requirements": [
                        {
                            "requirement_type": "staging",
                            "expected_value": [
                                "Ta",
                                "Tis",
                                "T1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Known history of human immunodeficiency virus (HIV) infection",
            "criterions": [
                {
                    "exact_snippets": "Known history of human immunodeficiency virus (HIV) infection",
                    "criterion": "HIV infection",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. Patients with seizure disorder requiring medication",
            "criterions": [
                {
                    "exact_snippets": "seizure disorder requiring medication",
                    "criterion": "seizure disorder",
                    "requirements": [
                        {
                            "requirement_type": "medication requirement",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "17. History of organ allograft",
            "criterions": [
                {
                    "exact_snippets": "History of organ allograft",
                    "criterion": "organ allograft",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "18. Patients with evidence or history of any bleeding diathesis, irrespective of severity",
            "criterions": [
                {
                    "exact_snippets": "evidence or history of any bleeding diathesis",
                    "criterion": "bleeding diathesis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "19. Any hemorrhage or bleeding event ≥ Grade 3, NCI-CTCAE v 4.0 within 4 weeks prior to the start of study medication",
            "criterions": [
                {
                    "exact_snippets": "Any hemorrhage or bleeding event ≥ Grade 3, NCI-CTCAE v 4.0 within 4 weeks prior to the start of study medication",
                    "criterion": "hemorrhage or bleeding event",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "Grade"
                            }
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 4 weeks prior to the start of study medication"
                        }
                    ]
                }
            ]
        },
        {
            "line": "20. Non-healing wound, non-healing ulcer or non-healing bone fracture",
            "criterions": [
                {
                    "exact_snippets": "Non-healing wound",
                    "criterion": "wound",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        }
                    ]
                },
                {
                    "exact_snippets": "non-healing ulcer",
                    "criterion": "ulcer",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        }
                    ]
                },
                {
                    "exact_snippets": "non-healing bone fracture",
                    "criterion": "bone fracture",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        }
                    ]
                }
            ]
        },
        {
            "line": "21. Dehydration grade ≥1, NCI-CTCAE v 4.0",
            "criterions": [
                {
                    "exact_snippets": "Dehydration grade ≥1, NCI-CTCAE v 4.0",
                    "criterion": "dehydration grade",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "NCI-CTCAE v 4.0"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "22. Known hypersensitivity to the study drug, study drug classes or excipient in the formulation",
            "criterions": [
                {
                    "exact_snippets": "Known hypersensitivity to the study drug",
                    "criterion": "hypersensitivity to study drug",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity to ... study drug classes",
                    "criterion": "hypersensitivity to study drug classes",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity to ... excipient in the formulation",
                    "criterion": "hypersensitivity to excipient in the formulation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "23. Interstitial lung disease with ongoing signs or symptoms at the time of inclusion",
            "criterions": [
                {
                    "exact_snippets": "Interstitial lung disease with ongoing signs or symptoms",
                    "criterion": "interstitial lung disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "ongoing"
                        }
                    ]
                }
            ]
        },
        {
            "line": "24. Persistent proteinuria >3.5 g/24 hour measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCI-CTCAE v 4.0)",
            "criterions": [
                {
                    "exact_snippets": "Persistent proteinuria >3.5 g/24 hour",
                    "criterion": "proteinuria",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 3.5,
                                "unit": "g/24 hour"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "urine protein-creatinine ratio from a random urine sample",
                    "criterion": "urine protein-creatinine ratio",
                    "requirements": [
                        {
                            "requirement_type": "measurement",
                            "expected_value": "random urine sample"
                        }
                    ]
                },
                {
                    "exact_snippets": "≥ Grade 3, NCI-CTCAE v 4.0",
                    "criterion": "NCI-CTCAE grade",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "Grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "25. Patients unable to swallow oral medication",
            "criterions": [
                {
                    "exact_snippets": "unable to swallow oral medication",
                    "criterion": "ability to swallow oral medication",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "26. Any malabsorption condition",
            "criterions": [
                {
                    "exact_snippets": "malabsorption condition",
                    "criterion": "malabsorption condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "27. Unresolved toxicity higher than Grade 1, NCI-CTCAE v 4.0, attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neuropathy",
            "criterions": [
                {
                    "exact_snippets": "Unresolved toxicity higher than Grade 1, NCI-CTCAE v 4.0",
                    "criterion": "unresolved toxicity",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 1,
                                "unit": "Grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "attributed to any prior therapy/procedure",
                    "criterion": "toxicity attribution",
                    "requirements": [
                        {
                            "requirement_type": "source",
                            "expected_value": "any prior therapy/procedure"
                        }
                    ]
                },
                {
                    "exact_snippets": "excluding alopecia and oxaliplatin induced neuropathy",
                    "criterion": "toxicity exclusion",
                    "requirements": [
                        {
                            "requirement_type": "conditions",
                            "expected_value": [
                                "alopecia",
                                "oxaliplatin induced neuropathy"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "29. Treatment with any other investigational medicinal product within 28 days prior to study entry",
            "criterions": [
                {
                    "exact_snippets": "Treatment with any other investigational medicinal product within 28 days prior to study entry",
                    "criterion": "treatment with investigational medicinal product",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": ">=",
                                "value": 28,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "30. Chronic treatment potentially interacting with the study medication, i.e. strong CYP3A4 inducers/inhibitors, strong UGT1A9 inhibitors",
            "criterions": [
                {
                    "exact_snippets": "Chronic treatment potentially interacting with the study medication, i.e. strong CYP3A4 inducers/inhibitors",
                    "criterion": "CYP3A4 interaction",
                    "requirements": [
                        {
                            "requirement_type": "interaction",
                            "expected_value": [
                                "strong inducer",
                                "strong inhibitor"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Chronic treatment potentially interacting with the study medication, i.e. ... strong UGT1A9 inhibitors",
                    "criterion": "UGT1A9 interaction",
                    "requirements": [
                        {
                            "requirement_type": "interaction",
                            "expected_value": "strong inhibitor"
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [
        {
            "line": "15. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy",
            "criterions": [
                {
                    "exact_snippets": "Active hepatitis B",
                    "criterion": "hepatitis B",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": "active"
                        }
                    ]
                },
                {
                    "exact_snippets": "Active ... hepatitis C",
                    "criterion": "hepatitis C",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": "active"
                        }
                    ]
                },
                {
                    "exact_snippets": "chronic hepatitis B",
                    "criterion": "hepatitis B",
                    "requirements": [
                        {
                            "requirement_type": "chronicity",
                            "expected_value": "chronic"
                        }
                    ]
                },
                {
                    "exact_snippets": "chronic hepatitis C",
                    "criterion": "hepatitis C",
                    "requirements": [
                        {
                            "requirement_type": "chronicity",
                            "expected_value": "chronic"
                        }
                    ]
                },
                {
                    "exact_snippets": "requiring treatment with antiviral therapy",
                    "criterion": "antiviral therapy",
                    "requirements": [
                        {
                            "requirement_type": "necessity",
                            "expected_value": "required"
                        }
                    ]
                }
            ]
        },
        {
            "line": "28. Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks",
            "criterions": [
                {
                    "exact_snippets": "Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks",
                    "criterion": "systemic anticancer therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "cytotoxic therapy during this trial or within 3 weeks",
                    "criterion": "cytotoxic therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "signal transduction inhibitors during this trial or within 3 weeks",
                    "criterion": "signal transduction inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "immunotherapy during this trial or within 3 weeks",
                    "criterion": "immunotherapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "hormonal therapy during this trial or within 3 weeks",
                    "criterion": "hormonal therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "failed_miscellaneous": []
}