{
    "info": {
        "nct_id": "NCT02448420",
        "official_title": "A Phase II Trial of Palbociclib in Combination With Trastuzumab and Endocrine Therapy in Patients With Previously-treated Locally Advanced or Metastatic HER2-positive Breast Cancer (PATRICIA II)",
        "inclusion_criteria": "Healthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "",
        "miscellaneous_criteria": "Inclusion Criteria\n\nFor Cohorts A and B (Recruitment Closed)\n\n1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.\n2. Female patients\n3. Age 18 years or older\n4. ECOG performance status 0 or 1.\n5. Invasive HER2 positive breast cancer, according to the local laboratory, defined according to ASCO/CAP criteria as:\n\n   1. 3+ overexpression on immunohistochemistry (>10% of invasive tumor cells with intensive, circumferential membrane staining)\n   2. Positive in situ hybridization (FISH/CISH/SISH) in >10% of invasive tumor cells, having counted at least 20 cells in the area and based on:\n\n   i. Single-probe HER2 gene copy number ≥ 6 signals/cell. ii. Dual-probe HER2/CEP17 ratio ≥ 2.0 with a mean HER2 gene copy number ≥ 4.0 signals/cell; HER2/CEP17 ratio ≥ 2.0 and < 4.0 signals/cell; and HER2/CEP17 ratio < 2.0 and ≥ 6.0 signals/cell.\n6. Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.\n7. Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced.\n\n   1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.\n   2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.\n8. All patients must have received at least 2 (maximum 4) previous lines of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab. Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.\n9. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor.\n10. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria. (Appendix 5).\n11. Adequate organ function, defined as:\n\n    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.\n    2. Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).\n    3. Platelets > 100,000/mm3.\n    4. Creatinine ≤ 1.5 x normal value\n    5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis).\n    6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.\n    7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).\n12. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).\n13. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study. ..14. Postmenopausal status defined as previous bilateral oophorectomy, age >60 or <60, and amenorrhoea for at least 12 months (in absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and FSH and estradiol in postmenopausal range, according to local laboratory.\n\nFor cohorts C:\n\n1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.\n2. Male or female patients. Premenopausal or postmenopausal women.\n3. Age 18 years or older.\n4. ECOG performance status 0 to 2.\n5. Invasive HER2 positive breast cancer, according to the central laboratory, defined according to ASCO/CAP criteria.\n6. Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.\n7. Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B).\n8. Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.\n\n   1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.\n   2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.\n9. All patients must have received at least 1 previous line of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab and/or anti-HER2 Antibody-Drug conjugate). Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including but not limited to lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted. Also patients who recur during or within 12 months after completing adjuvant treatment with trastuzumab and/or antiHER2-ADCs (including but not limited to T-DM1) can be enrolled in the moment of the diagnosis of metastatic disease.\n10. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumour.\n11. Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria.\n12. Adequate organ function, defined as:\n\n    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.\n    2. Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).\n    3. Platelets > 100,000/mm3\n    4. Creatinine ≤ 1.5 x normal value\n    5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)\n    6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.\n    7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).\n13. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).\n14. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study.\n15. If female of childbearing potential, must have a negative result of serum pregnancy test performed within 7 days prior to the first dose of study treatment.\n16. Participants with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:\n\n    * Disease outside the CNS is present.\n    * No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.\n    * No history of intracranial hemorrhage or spinal cord hemorrhage.\n    * Stable doses or no need of corticosteroids and anti-convulsants for symptomatic control\n    * Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of study treatment; and recovery from any significant (Grade ≥ 3) acute toxicity\n\nExclusion criteria\n\nFor cohorts A, B (Recruitment Closed)\n\n1. Treatment with any investigational anticancer drug within 14 days of the start of study treatment.\n2. Patient has received more than 4 previous lines of treatment (anti-HER2 drug +/- chemotherapy) for metastatic breast cancer or locally advanced disease. Exclusively hormonal treatments will not be taken into account.\n3. Previous treatment with a cyclin-dependent kinase inhibitor.\n4. History of other malignant tumours in the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumours with an expected curative outcome.\n5. Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to > 30% of the bone marrow.\n6. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Biphosphonates will be permitted for the prevention of bone events.\n7. History of exposure to cumulative anthracycline doses greater than follows:\n\n   1. Adriamycin > 400 mg/m2\n   2. Epirubicin > 720 mg/m2\n   3. Mitoxantrone > 120 mg/m2\n   4. Idarubicin > 90 mg/m2\n   5. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.\n8. Cardiopulmonary dysfunction, defined as:\n\n   1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment.\n   2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.\n   3. History of congestive heart failure NCI CTCAE version 4.0 grade ≥ 3 NYHA class ≥ 2.\n   4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.\n   5. Myocardial infarction within 6 months before randomisation.\n   6. Resting dyspnoea due to complications of the malignant disease, requiring continuous oxygen therapy.\n9. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or haematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).\n10. Major surgery in the 28 days prior to randomisation or foreseeable during study treatment period.\n11. Infection with HIV or active Hepatitis B and/or Hepatitis C.\n12. History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.\n13. Known hypersensitivity to any of the study drugs, including inactive ingredients.\n14. Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.\n\nExclusion criteria Cohort C\n\n1. Treatment with any investigational anticancer drug within 14 days of the start of study treatment.\n2. Previous treatment with a cyclin-dependent kinase inhibitor.\n3. History of other malignant tumors in the past 3 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumors with an expected curative outcome.\n4. Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to > 30% of the bone marrow.\n5. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Bisphosphonates or RANKL inhibitors will be permitted for the prevention of bone events.\n6. History of exposure to cumulative anthracycline doses greater than follows:\n\n   1. Adriamycin > 400 mg/m2\n   2. Epirubicin > 720 mg/m2\n   3. Mitoxantrone > 120 mg/m2\n   4. Idarubicin > 90 mg/m2\n   5. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.\n7. Cardiopulmonary dysfunction, defined as:\n\n   1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment.\n   2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.\n   3. History of congestive heart failure NCI CTCAE version 5.0 grade ≥ 3 NYHA class ≥ 2.\n   4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.\n   5. Myocardial infarction within 6 months before randomization.\n   6. Resting dyspnea due to complications of the malignant disease, requiring continuous oxygen therapy.\n8. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or hematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).\n9. Major surgery in the 28 days prior to randomization or foreseeable during study treatment period.\n10. Infection with HIV or active Hepatitis B and/or Hepatitis C.\n11. History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.\n12. Known hypersensitivity to any of the study drugs, including inactive ingredients.\n13. Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.\n\nIn cohort C, patients that are initially allocated in the control arm (physician's treatment choice) and have a documented disease progression can be re-randomized to receive the experimental or control treatment (if they meet the inclusion criteria after progression)."
    },
    "inclusion_lines": [
        {
            "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": [],
    "miscellaneous_lines": [
        {
            "line": "For Cohorts A and B (Recruitment Closed)",
            "criterions": [
                {
                    "exact_snippets": "Cohorts A and B",
                    "criterion": "cohort",
                    "requirements": [
                        {
                            "requirement_type": "recruitment status",
                            "expected_value": "closed"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.",
            "criterions": [
                {
                    "exact_snippets": "Written signed Informed Consent",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Female patients",
            "criterions": [
                {
                    "exact_snippets": "Female patients",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "expected_value",
                            "expected_value": "female"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Age 18 years or older",
            "criterions": [
                {
                    "exact_snippets": "Age 18 years or older",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. ECOG performance status 0 or 1.",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status 0 or 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Invasive HER2 positive breast cancer, according to the local laboratory, defined according to ASCO/CAP criteria as:",
            "criterions": [
                {
                    "exact_snippets": "Invasive HER2 positive breast cancer",
                    "criterion": "HER2 status",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "Invasive HER2 positive breast cancer",
                    "criterion": "breast cancer type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "invasive"
                        }
                    ]
                },
                {
                    "exact_snippets": "according to the local laboratory",
                    "criterion": "HER2 status determination",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "local laboratory"
                        }
                    ]
                },
                {
                    "exact_snippets": "defined according to ASCO/CAP criteria",
                    "criterion": "HER2 status determination",
                    "requirements": [
                        {
                            "requirement_type": "standard",
                            "expected_value": "ASCO/CAP criteria"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. 3+ overexpression on immunohistochemistry (>10% of invasive tumor cells with intensive, circumferential membrane staining)",
            "criterions": [
                {
                    "exact_snippets": "3+ overexpression on immunohistochemistry (>10% of invasive tumor cells with intensive, circumferential membrane staining)",
                    "criterion": "overexpression on immunohistochemistry",
                    "requirements": [
                        {
                            "requirement_type": "intensity",
                            "expected_value": "3+"
                        },
                        {
                            "requirement_type": "percentage of invasive tumor cells",
                            "expected_value": {
                                "operator": ">",
                                "value": 10,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Positive in situ hybridization (FISH/CISH/SISH) in >10% of invasive tumor cells, having counted at least 20 cells in the area and based on:",
            "criterions": [
                {
                    "exact_snippets": "Positive in situ hybridization (FISH/CISH/SISH)",
                    "criterion": "in situ hybridization",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "in >10% of invasive tumor cells",
                    "criterion": "invasive tumor cells",
                    "requirements": [
                        {
                            "requirement_type": "percentage",
                            "expected_value": {
                                "operator": ">",
                                "value": 10,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "having counted at least 20 cells in the area",
                    "criterion": "cell count",
                    "requirements": [
                        {
                            "requirement_type": "minimum count",
                            "expected_value": {
                                "operator": ">=",
                                "value": 20,
                                "unit": "cells"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "i. Single-probe HER2 gene copy number ≥ 6 signals/cell. ii. Dual-probe HER2/CEP17 ratio ≥ 2.0 with a mean HER2 gene copy number ≥ 4.0 signals/cell; HER2/CEP17 ratio ≥ 2.0 and < 4.0 signals/cell; and HER2/CEP17 ratio < 2.0 and ≥ 6.0 signals/cell.",
            "criterions": [
                {
                    "exact_snippets": "Single-probe HER2 gene copy number ≥ 6 signals/cell",
                    "criterion": "HER2 gene copy number (single-probe)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 6,
                                "unit": "signals/cell"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Dual-probe HER2/CEP17 ratio ≥ 2.0 with a mean HER2 gene copy number ≥ 4.0 signals/cell",
                    "criterion": "HER2/CEP17 ratio (dual-probe) and mean HER2 gene copy number",
                    "requirements": [
                        {
                            "requirement_type": "ratio",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2.0,
                                "unit": "N/A"
                            }
                        },
                        {
                            "requirement_type": "mean quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 4.0,
                                "unit": "signals/cell"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "HER2/CEP17 ratio ≥ 2.0 and < 4.0 signals/cell",
                    "criterion": "HER2/CEP17 ratio (dual-probe)",
                    "requirements": [
                        {
                            "requirement_type": "ratio",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 2.0,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "<",
                                        "value": 4.0,
                                        "unit": "signals/cell"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "HER2/CEP17 ratio < 2.0 and ≥ 6.0 signals/cell",
                    "criterion": "HER2/CEP17 ratio (dual-probe)",
                    "requirements": [
                        {
                            "requirement_type": "ratio",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 2.0,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": ">=",
                                        "value": 6.0,
                                        "unit": "signals/cell"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.",
            "criterions": [
                {
                    "exact_snippets": "Known hormone receptor, determined locally according to ASCO/CAP guidelines",
                    "criterion": "hormone receptor status",
                    "requirements": [
                        {
                            "requirement_type": "determination",
                            "expected_value": "locally according to ASCO/CAP guidelines"
                        }
                    ]
                },
                {
                    "exact_snippets": "OR or PgR considered positive in case of ≥1% of cell nuclei positive",
                    "criterion": "OR or PgR status",
                    "requirements": [
                        {
                            "requirement_type": "positivity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "% of cell nuclei"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced.",
            "criterions": [
                {
                    "exact_snippets": "Histologically-confirmed adenocarcinoma of the breast",
                    "criterion": "adenocarcinoma of the breast",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": "histologically-confirmed"
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic or locally advanced",
                    "criterion": "cancer stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": [
                                "metastatic",
                                "locally advanced"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.",
            "criterions": [
                {
                    "exact_snippets": "locally advanced disease",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "recurrent or progressive disease",
                    "criterion": "disease progression",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unsuitable for resection with curative intent",
                    "criterion": "suitability for resection",
                    "requirements": [
                        {
                            "requirement_type": "suitability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "standard curative options available",
                    "criterion": "availability of standard curative options",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.",
            "criterions": [
                {
                    "exact_snippets": "bilateral breast cancer",
                    "criterion": "bilateral breast cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HER2+ positivity must be demonstrated",
                    "criterion": "HER2+ positivity",
                    "requirements": [
                        {
                            "requirement_type": "demonstration",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in both sites or in a metastatic biopsy",
                    "criterion": "HER2+ positivity location",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "both sites",
                                "metastatic biopsy"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. All patients must have received at least 2 (maximum 4) previous lines of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab. Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.",
            "criterions": [
                {
                    "exact_snippets": "received at least 2 (maximum 4) previous lines of systemic treatment",
                    "criterion": "previous lines of systemic treatment",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 2,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 4,
                                        "unit": "N/A"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "previous lines of systemic treatment ... at least one of which must have included trastuzumab",
                    "criterion": "trastuzumab in previous treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including lapatinib, neratinib, pertuzumab or T-DM1",
                    "criterion": "previous use of anti-HER2 treatment",
                    "requirements": [
                        {
                            "requirement_type": "permitted",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous use of any chemotherapy or hormone agent is permitted",
                    "criterion": "previous use of chemotherapy or hormone agent",
                    "requirements": [
                        {
                            "requirement_type": "permitted",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor.",
            "criterions": [
                {
                    "exact_snippets": "Tumour tissue available for biomarker analysis",
                    "criterion": "tumor tissue",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "obtained from metastatic lesions (preferably) or from the primary tumor",
                    "criterion": "source of tumor tissue",
                    "requirements": [
                        {
                            "requirement_type": "preference",
                            "expected_value": "metastatic lesions"
                        },
                        {
                            "requirement_type": "alternative",
                            "expected_value": "primary tumor"
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria. (Appendix 5).",
            "criterions": [
                {
                    "exact_snippets": "Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria.",
                    "criterion": "disease measurability",
                    "requirements": [
                        {
                            "requirement_type": "criteria",
                            "expected_value": [
                                "measurable",
                                "non-measurable (but evaluable)"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Adequate organ function, defined as:",
            "criterions": [
                {
                    "exact_snippets": "Adequate organ function",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) ≥ 1.5 x 109/L",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).",
            "criterions": [
                {
                    "exact_snippets": "Haemoglobin (Hb) ≥9 g/dl",
                    "criterion": "haemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dl"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Platelets > 100,000/mm3.",
            "criterions": [
                {
                    "exact_snippets": "Platelets > 100,000/mm3",
                    "criterion": "platelets",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 100000,
                                "unit": "mm3"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Creatinine ≤ 1.5 x normal value",
            "criterions": [
                {
                    "exact_snippets": "Creatinine ≤ 1.5 x normal value",
                    "criterion": "creatinine level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x normal value"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis).",
            "criterions": [
                {
                    "exact_snippets": "AST or ALT ≤ 2.5 x ULN",
                    "criterion": "AST or ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "AST or ALT ... ≤5 x ULN in case of liver metastasis",
                    "criterion": "AST or ALT levels in case of liver metastasis",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.",
            "criterions": [
                {
                    "exact_snippets": "Alkaline phosphatase ≤2.5 x ULN",
                    "criterion": "alkaline phosphatase",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases",
                    "criterion": "alkaline phosphatase",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": "> 2.5 x ULN only in the case of bone metastases"
                        }
                    ]
                },
                {
                    "exact_snippets": "AST and ALT less than 1.5 x ULN",
                    "criterion": "AST and ALT",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin ≤1.5 mg/dl",
                    "criterion": "total bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "mg/dl"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "higher bilirubin levels are permitted if the patient has Gilbert's syndrome",
                    "criterion": "Gilbert's syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).",
            "criterions": [
                {
                    "exact_snippets": "Baseline LVEF ≥50%",
                    "criterion": "LVEF",
                    "requirements": [
                        {
                            "requirement_type": "baseline measurement",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "measured using echocardiogram or equilibrium isotopic ventriculography (MUGA)",
                    "criterion": "LVEF measurement method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "echocardiogram",
                                "equilibrium isotopic ventriculography (MUGA)"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study. ..14. Postmenopausal status defined as previous bilateral oophorectomy, age >60 or <60, and amenorrhoea for at least 12 months (in absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and FSH and estradiol in postmenopausal range, according to local laboratory.",
            "criterions": [
                {
                    "exact_snippets": "Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule.",
                    "criterion": "psychological, family, sociological or geographical conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Postmenopausal status defined as previous bilateral oophorectomy",
                    "criterion": "postmenopausal status",
                    "requirements": [
                        {
                            "requirement_type": "definition",
                            "expected_value": "previous bilateral oophorectomy"
                        }
                    ]
                },
                {
                    "exact_snippets": "Postmenopausal status defined as ... age >60",
                    "criterion": "postmenopausal status",
                    "requirements": [
                        {
                            "requirement_type": "definition",
                            "expected_value": {
                                "operator": ">",
                                "value": 60,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Postmenopausal status defined as ... <60, and amenorrhoea for at least 12 months",
                    "criterion": "postmenopausal status",
                    "requirements": [
                        {
                            "requirement_type": "definition",
                            "expected_value": [
                                ">60 years",
                                "<60 years and amenorrhoea for at least 12 months"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "amenorrhoea for at least 12 months (in absence of chemotherapy, tamoxifen, toremifene or ovarian suppression)",
                    "criterion": "amenorrhoea",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 12,
                                "unit": "months"
                            }
                        },
                        {
                            "requirement_type": "absence",
                            "expected_value": [
                                "chemotherapy",
                                "tamoxifen",
                                "toremifene",
                                "ovarian suppression"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "FSH and estradiol in postmenopausal range, according to local laboratory.",
                    "criterion": "FSH and estradiol levels",
                    "requirements": [
                        {
                            "requirement_type": "range",
                            "expected_value": "postmenopausal range according to local laboratory"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.",
            "criterions": [
                {
                    "exact_snippets": "Written signed Informed Consent",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Male or female patients. Premenopausal or postmenopausal women.",
            "criterions": [
                {
                    "exact_snippets": "Male or female patients",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": [
                                "male",
                                "female"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Premenopausal or postmenopausal women",
                    "criterion": "menopausal status",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": [
                                "premenopausal",
                                "postmenopausal"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Age 18 years or older.",
            "criterions": [
                {
                    "exact_snippets": "Age 18 years or older.",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. ECOG performance status 0 to 2.",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status 0 to 2",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "range",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 0,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 2,
                                        "unit": "N/A"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Invasive HER2 positive breast cancer, according to the central laboratory, defined according to ASCO/CAP criteria.",
            "criterions": [
                {
                    "exact_snippets": "Invasive HER2 positive breast cancer",
                    "criterion": "HER2 status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "Invasive HER2 positive breast cancer",
                    "criterion": "breast cancer type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "invasive"
                        }
                    ]
                },
                {
                    "exact_snippets": "according to the central laboratory",
                    "criterion": "HER2 status determination",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "central laboratory"
                        }
                    ]
                },
                {
                    "exact_snippets": "defined according to ASCO/CAP criteria",
                    "criterion": "HER2 status determination",
                    "requirements": [
                        {
                            "requirement_type": "criteria",
                            "expected_value": "ASCO/CAP"
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of ≥1% of cell nuclei positive.",
            "criterions": [
                {
                    "exact_snippets": "Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines",
                    "criterion": "hormone receptor status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        },
                        {
                            "requirement_type": "determination method",
                            "expected_value": "locally according to ASCO/CAP guidelines"
                        }
                    ]
                },
                {
                    "exact_snippets": "PgR considered positive in case of ≥1% of cell nuclei positive",
                    "criterion": "PgR status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        },
                        {
                            "requirement_type": "percentage of cell nuclei positive",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B).",
            "criterions": [
                {
                    "exact_snippets": "Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B)",
                    "criterion": "Luminal intrinsic subtype",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": "centrally confirmed"
                        },
                        {
                            "requirement_type": "subtype",
                            "expected_value": [
                                "Luminal A",
                                "Luminal B"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.",
            "criterions": [
                {
                    "exact_snippets": "Histologically confirmed adenocarcinoma of the breast",
                    "criterion": "adenocarcinoma of the breast",
                    "requirements": [
                        {
                            "requirement_type": "confirmation method",
                            "expected_value": "histologically confirmed"
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic or locally advanced",
                    "criterion": "cancer stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": [
                                "metastatic",
                                "locally advanced"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible.",
            "criterions": [
                {
                    "exact_snippets": "locally advanced disease",
                    "criterion": "locally advanced disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "recurrent or progressive disease",
                    "criterion": "recurrent or progressive disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unsuitable for resection with curative intent",
                    "criterion": "suitability for resection with curative intent",
                    "requirements": [
                        {
                            "requirement_type": "suitability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "standard curative options available",
                    "criterion": "availability of standard curative options",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy.",
            "criterions": [
                {
                    "exact_snippets": "bilateral breast cancer",
                    "criterion": "bilateral breast cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HER2+ positivity must be demonstrated",
                    "criterion": "HER2+ positivity",
                    "requirements": [
                        {
                            "requirement_type": "demonstration",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in both sites or in a metastatic biopsy",
                    "criterion": "HER2+ positivity location",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "both sites",
                                "metastatic biopsy"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. All patients must have received at least 1 previous line of systemic treatment for metastatic or locally advanced disease, at least one of which must have included trastuzumab and/or anti-HER2 Antibody-Drug conjugate). Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted, including but not limited to lapatinib, neratinib, pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted. Also patients who recur during or within 12 months after completing adjuvant treatment with trastuzumab and/or antiHER2-ADCs (including but not limited to T-DM1) can be enrolled in the moment of the diagnosis of metastatic disease.",
            "criterions": [
                {
                    "exact_snippets": "All patients must have received at least 1 previous line of systemic treatment",
                    "criterion": "previous systemic treatment",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "lines"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "at least one of which must have included trastuzumab and/or anti-HER2 Antibody-Drug conjugate",
                    "criterion": "previous treatment with trastuzumab or anti-HER2 ADC",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous use of other anti-HER2 treatment, alone or in combination with chemotherapy, is permitted",
                    "criterion": "previous anti-HER2 treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous use of any chemotherapy or hormone agent is permitted",
                    "criterion": "previous chemotherapy or hormone agent use",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who recur during or within 12 months after completing adjuvant treatment with trastuzumab and/or antiHER2-ADCs",
                    "criterion": "recurrence after adjuvant treatment with trastuzumab or anti-HER2 ADCs",
                    "requirements": [
                        {
                            "requirement_type": "time since completion",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 12,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumour.",
            "criterions": [
                {
                    "exact_snippets": "Tumour tissue available for biomarker analysis",
                    "criterion": "tumour tissue",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "obtained from metastatic lesions (preferably) or from the primary tumour",
                    "criterion": "source of tumour tissue",
                    "requirements": [
                        {
                            "requirement_type": "preference",
                            "expected_value": "metastatic lesions"
                        },
                        {
                            "requirement_type": "alternative",
                            "expected_value": "primary tumour"
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria.",
            "criterions": [
                {
                    "exact_snippets": "Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria.",
                    "criterion": "disease measurability",
                    "requirements": [
                        {
                            "requirement_type": "criteria",
                            "expected_value": [
                                "measurable",
                                "non-measurable (but evaluable)"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "according to RECIST 1.1 criteria.",
                    "criterion": "RECIST 1.1 criteria",
                    "requirements": [
                        {
                            "requirement_type": "compliance",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Adequate organ function, defined as:",
            "criterions": [
                {
                    "exact_snippets": "Adequate organ function",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) ≥ 1.5 x 109/L",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin (Hb) ≥9 g/dl",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dl"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Platelets > 100,000/mm3",
            "criterions": [
                {
                    "exact_snippets": "Platelets > 100,000/mm3",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 100000,
                                "unit": "mm3"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Creatinine ≤ 1.5 x normal value",
            "criterions": [
                {
                    "exact_snippets": "Creatinine ≤ 1.5 x normal value",
                    "criterion": "creatinine level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x normal value"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)",
            "criterions": [
                {
                    "exact_snippets": "AST or ALT ≤ 2.5 x ULN",
                    "criterion": "AST or ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "AST or ALT ... ≤5 x ULN in case of liver metastasis",
                    "criterion": "AST or ALT levels in case of liver metastasis",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.",
            "criterions": [
                {
                    "exact_snippets": "Alkaline phosphatase ≤2.5 x ULN",
                    "criterion": "alkaline phosphatase",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases",
                    "criterion": "alkaline phosphatase",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": "may be more than 2.5 x ULN only in the case of bone metastases"
                        }
                    ]
                },
                {
                    "exact_snippets": "AST and ALT less than 1.5 x ULN",
                    "criterion": "AST and ALT",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin ≤1.5 mg/dl",
                    "criterion": "total bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "mg/dl"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "higher bilirubin levels are permitted if the patient has Gilbert's syndrome",
                    "criterion": "Gilbert's syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).",
            "criterions": [
                {
                    "exact_snippets": "Baseline LVEF ≥50%",
                    "criterion": "baseline LVEF",
                    "requirements": [
                        {
                            "requirement_type": "measurement",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "measured using echocardiogram or equilibrium isotopic ventriculography (MUGA)",
                    "criterion": "LVEF measurement method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "echocardiogram",
                                "equilibrium isotopic ventriculography (MUGA)"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study.",
            "criterions": [
                {
                    "exact_snippets": "Absence of psychological ... conditions that could potentially hinder compliance",
                    "criterion": "psychological conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of ... family ... conditions that could potentially hinder compliance",
                    "criterion": "family conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of ... sociological ... conditions that could potentially hinder compliance",
                    "criterion": "sociological conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of ... geographical conditions that could potentially hinder compliance",
                    "criterion": "geographical conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "15. If female of childbearing potential, must have a negative result of serum pregnancy test performed within 7 days prior to the first dose of study treatment.",
            "criterions": [
                {
                    "exact_snippets": "female of childbearing potential",
                    "criterion": "female of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "negative result of serum pregnancy test",
                    "criterion": "serum pregnancy test result",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                },
                {
                    "exact_snippets": "performed within 7 days prior to the first dose of study treatment",
                    "criterion": "timing of serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 7 days prior to the first dose of study treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. Participants with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:",
            "criterions": [
                {
                    "exact_snippets": "history of treated CNS metastases",
                    "criterion": "CNS metastases",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment_status",
                            "expected_value": "treated"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Disease outside the CNS is present.",
            "criterions": [
                {
                    "exact_snippets": "Disease outside the CNS is present.",
                    "criterion": "disease outside the CNS",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.",
            "criterions": [
                {
                    "exact_snippets": "No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.",
                    "criterion": "interim progression",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* No history of intracranial hemorrhage or spinal cord hemorrhage.",
            "criterions": [
                {
                    "exact_snippets": "No history of intracranial hemorrhage",
                    "criterion": "intracranial hemorrhage",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "No history of ... spinal cord hemorrhage",
                    "criterion": "spinal cord hemorrhage",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Stable doses or no need of corticosteroids and anti-convulsants for symptomatic control",
            "criterions": [
                {
                    "exact_snippets": "Stable doses or no need of corticosteroids",
                    "criterion": "corticosteroids",
                    "requirements": [
                        {
                            "requirement_type": "dose stability",
                            "expected_value": "stable"
                        },
                        {
                            "requirement_type": "necessity",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Stable doses or no need of ... anti-convulsants for symptomatic control",
                    "criterion": "anti-convulsants",
                    "requirements": [
                        {
                            "requirement_type": "dose stability",
                            "expected_value": "stable"
                        },
                        {
                            "requirement_type": "necessity",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of study treatment; and recovery from any significant (Grade ≥ 3) acute toxicity",
            "criterions": [
                {
                    "exact_snippets": "Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of study treatment",
                    "criterion": "time since CNS radiotherapy",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "recovery from any significant (Grade ≥ 3) acute toxicity",
                    "criterion": "recovery from acute toxicity",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "Grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "For cohorts A, B (Recruitment Closed)",
            "criterions": [
                {
                    "exact_snippets": "cohorts A, B",
                    "criterion": "cohort",
                    "requirements": [
                        {
                            "requirement_type": "membership",
                            "expected_value": [
                                "A",
                                "B"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Recruitment Closed",
                    "criterion": "recruitment status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "closed"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Treatment with any investigational anticancer drug within 14 days of the start of study treatment.",
            "criterions": [
                {
                    "exact_snippets": "Treatment with any investigational anticancer drug within 14 days of the start of study treatment.",
                    "criterion": "treatment with investigational anticancer drug",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Patient has received more than 4 previous lines of treatment (anti-HER2 drug +/- chemotherapy) for metastatic breast cancer or locally advanced disease. Exclusively hormonal treatments will not be taken into account.",
            "criterions": [
                {
                    "exact_snippets": "Patient has received more than 4 previous lines of treatment",
                    "criterion": "previous lines of treatment",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 4,
                                "unit": "lines"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "anti-HER2 drug +/- chemotherapy",
                    "criterion": "type of previous treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": [
                                "anti-HER2 drug",
                                "chemotherapy"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic breast cancer or locally advanced disease",
                    "criterion": "disease status",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": [
                                "metastatic breast cancer",
                                "locally advanced disease"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Exclusively hormonal treatments will not be taken into account",
                    "criterion": "hormonal treatments",
                    "requirements": [
                        {
                            "requirement_type": "exclusion",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Previous treatment with a cyclin-dependent kinase inhibitor.",
            "criterions": [
                {
                    "exact_snippets": "Previous treatment with a cyclin-dependent kinase inhibitor.",
                    "criterion": "treatment with a cyclin-dependent kinase inhibitor",
                    "requirements": [
                        {
                            "requirement_type": "previous treatment",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. History of other malignant tumours in the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumours with an expected curative outcome.",
            "criterions": [
                {
                    "exact_snippets": "History of other malignant tumours in the past 5 years",
                    "criterion": "history of malignant tumours",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "years"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "adequately treated in situ carcinoma of the cervix",
                    "criterion": "in situ carcinoma of the cervix",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "adequately treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "non-melanoma carcinoma of the skin",
                    "criterion": "non-melanoma carcinoma of the skin",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uterine cancer in stage I",
                    "criterion": "uterine cancer",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "I"
                        }
                    ]
                },
                {
                    "exact_snippets": "other malignant tumours with an expected curative outcome",
                    "criterion": "other malignant tumours",
                    "requirements": [
                        {
                            "requirement_type": "expected outcome",
                            "expected_value": "curative"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to > 30% of the bone marrow.",
            "criterions": [
                {
                    "exact_snippets": "Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study",
                    "criterion": "radiation therapy for metastases outside the brain",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 21,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who have received radiation to > 30% of the bone marrow",
                    "criterion": "radiation to bone marrow",
                    "requirements": [
                        {
                            "requirement_type": "extent of radiation",
                            "expected_value": {
                                "operator": ">",
                                "value": 30,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Biphosphonates will be permitted for the prevention of bone events.",
            "criterions": [
                {
                    "exact_snippets": "Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study",
                    "criterion": "symptomatic hypercalcemia",
                    "requirements": [
                        {
                            "requirement_type": "treatment requirement",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment type",
                            "expected_value": "bisphosphonates"
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 21,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. History of exposure to cumulative anthracycline doses greater than follows:",
            "criterions": [
                {
                    "exact_snippets": "History of exposure to cumulative anthracycline doses greater than",
                    "criterion": "cumulative anthracycline doses",
                    "requirements": [
                        {
                            "requirement_type": "exposure",
                            "expected_value": {
                                "operator": ">",
                                "value": 0,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Adriamycin > 400 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Adriamycin > 400 mg/m2",
                    "criterion": "Adriamycin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 400,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Epirubicin > 720 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Epirubicin > 720 mg/m2",
                    "criterion": "Epirubicin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 720,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Mitoxantrone > 120 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Mitoxantrone > 120 mg/m2",
                    "criterion": "Mitoxantrone dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 120,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Idarubicin > 90 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Idarubicin > 90 mg/m2",
                    "criterion": "Idarubicin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 90,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.",
            "criterions": [
                {
                    "exact_snippets": "If another anthracycline or more than one anthracycline has been used",
                    "criterion": "anthracycline usage",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin",
                    "criterion": "cumulative dose of anthracycline",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 400,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Cardiopulmonary dysfunction, defined as:",
            "criterions": [
                {
                    "exact_snippets": "Cardiopulmonary dysfunction",
                    "criterion": "cardiopulmonary dysfunction",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment.",
            "criterions": [
                {
                    "exact_snippets": "Uncontrolled hypertension",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "systolic > 150 mmHg",
                    "criterion": "systolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 150,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "diastolic > 100 mmHg",
                    "criterion": "diastolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 100,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "despite optimum medical treatment",
                    "criterion": "medical treatment",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": "optimum"
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.",
            "criterions": [
                {
                    "exact_snippets": "Angina pectoris ... poorly controlled with optimum medical treatment",
                    "criterion": "angina pectoris",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "poorly controlled with optimum medical treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "arrhythmia poorly controlled with optimum medical treatment",
                    "criterion": "arrhythmia",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "poorly controlled with optimum medical treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. History of congestive heart failure NCI CTCAE version 4.0 grade ≥ 3 NYHA class ≥ 2.",
            "criterions": [
                {
                    "exact_snippets": "History of congestive heart failure",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "NCI CTCAE version 4.0 grade ≥ 3",
                    "criterion": "NCI CTCAE grade for congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "N/A"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "NYHA class ≥ 2",
                    "criterion": "NYHA class for congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.",
            "criterions": [
                {
                    "exact_snippets": "History of LVEF decrease to < 40%",
                    "criterion": "LVEF decrease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<",
                                "value": 40,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "symptomatic congestive heart failure during prior treatment with trastuzumab",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "trastuzumab"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Myocardial infarction within 6 months before randomisation.",
            "criterions": [
                {
                    "exact_snippets": "Myocardial infarction within 6 months before randomisation.",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 6,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Resting dyspnoea due to complications of the malignant disease, requiring continuous oxygen therapy.",
            "criterions": [
                {
                    "exact_snippets": "Resting dyspnoea due to complications of the malignant disease",
                    "criterion": "resting dyspnoea",
                    "requirements": [
                        {
                            "requirement_type": "cause",
                            "expected_value": "complications of the malignant disease"
                        }
                    ]
                },
                {
                    "exact_snippets": "requiring continuous oxygen therapy",
                    "criterion": "oxygen therapy",
                    "requirements": [
                        {
                            "requirement_type": "necessity",
                            "expected_value": "continuous"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or haematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).",
            "criterions": [
                {
                    "exact_snippets": "severe, uncontrolled disease ... pulmonary",
                    "criterion": "pulmonary disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... cardiac",
                    "criterion": "cardiac disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... metabolic",
                    "criterion": "metabolic disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... haematological disorder",
                    "criterion": "haematological disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... wound healing disorders",
                    "criterion": "wound healing disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... ulcers",
                    "criterion": "ulcers",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... bone fractures",
                    "criterion": "bone fractures",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... infectious processes",
                    "criterion": "infectious processes",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Major surgery in the 28 days prior to randomisation or foreseeable during study treatment period.",
            "criterions": [
                {
                    "exact_snippets": "Major surgery in the 28 days prior to randomisation",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "time since occurrence",
                            "expected_value": {
                                "operator": "<=",
                                "value": 28,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "foreseeable during study treatment period",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "foreseeability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Infection with HIV or active Hepatitis B and/or Hepatitis C.",
            "criterions": [
                {
                    "exact_snippets": "Infection with HIV",
                    "criterion": "HIV infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "active Hepatitis B",
                    "criterion": "active Hepatitis B",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "active ... Hepatitis C",
                    "criterion": "active Hepatitis C",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.",
            "criterions": [
                {
                    "exact_snippets": "History of trastuzumab intolerance",
                    "criterion": "trastuzumab intolerance",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "grade 3-4 infusion reaction",
                    "criterion": "infusion reaction",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 3,
                                        "unit": "grade"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 4,
                                        "unit": "grade"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity",
                    "criterion": "hypersensitivity",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Known hypersensitivity to any of the study drugs, including inactive ingredients.",
            "criterions": [
                {
                    "exact_snippets": "Known hypersensitivity to any of the study drugs",
                    "criterion": "hypersensitivity to study drugs",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity to ... inactive ingredients",
                    "criterion": "hypersensitivity to inactive ingredients",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.",
            "criterions": [
                {
                    "exact_snippets": "Inability, in the opinion of the investigator, to comply with the protocol requirements",
                    "criterion": "ability to comply with protocol requirements",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder study follow-up",
                    "criterion": "comorbidity hindering study follow-up",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder ... response evaluation",
                    "criterion": "comorbidity hindering response evaluation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder ... the informed consent process",
                    "criterion": "comorbidity hindering informed consent process",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "Exclusion criteria Cohort C",
            "criterions": [
                {
                    "exact_snippets": "Exclusion criteria Cohort C",
                    "criterion": "cohort",
                    "requirements": [
                        {
                            "requirement_type": "exclusion",
                            "expected_value": "C"
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Treatment with any investigational anticancer drug within 14 days of the start of study treatment.",
            "criterions": [
                {
                    "exact_snippets": "Treatment with any investigational anticancer drug within 14 days of the start of study treatment.",
                    "criterion": "treatment with investigational anticancer drug",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Previous treatment with a cyclin-dependent kinase inhibitor.",
            "criterions": [
                {
                    "exact_snippets": "Previous treatment with a cyclin-dependent kinase inhibitor.",
                    "criterion": "treatment with a cyclin-dependent kinase inhibitor",
                    "requirements": [
                        {
                            "requirement_type": "previous treatment",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. History of other malignant tumors in the past 3 years, with the exception of adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumors with an expected curative outcome.",
            "criterions": [
                {
                    "exact_snippets": "History of other malignant tumors in the past 3 years",
                    "criterion": "history of malignant tumors",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 3,
                                        "unit": "years"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "adequately treated in situ carcinoma of the cervix",
                    "criterion": "in situ carcinoma of the cervix",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "adequately treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "non-melanoma carcinoma of the skin",
                    "criterion": "non-melanoma carcinoma of the skin",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "uterine cancer in stage I",
                    "criterion": "uterine cancer",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "I"
                        }
                    ]
                },
                {
                    "exact_snippets": "other malignant tumors with an expected curative outcome",
                    "criterion": "other malignant tumors",
                    "requirements": [
                        {
                            "requirement_type": "expected outcome",
                            "expected_value": "curative"
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to > 30% of the bone marrow.",
            "criterions": [
                {
                    "exact_snippets": "Radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study",
                    "criterion": "radiation therapy for metastases outside the brain",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 21,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who have received radiation to > 30% of the bone marrow",
                    "criterion": "radiation to bone marrow",
                    "requirements": [
                        {
                            "requirement_type": "extent of radiation",
                            "expected_value": {
                                "operator": ">",
                                "value": 30,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study. Bisphosphonates or RANKL inhibitors will be permitted for the prevention of bone events.",
            "criterions": [
                {
                    "exact_snippets": "Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days prior to inclusion in the study.",
                    "criterion": "symptomatic hypercalcemia",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": "bisphosphonates"
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "21 days prior to inclusion"
                        }
                    ]
                },
                {
                    "exact_snippets": "Bisphosphonates or RANKL inhibitors will be permitted for the prevention of bone events.",
                    "criterion": "prevention of bone events",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": [
                                "bisphosphonates",
                                "RANKL inhibitors"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. History of exposure to cumulative anthracycline doses greater than follows:",
            "criterions": [
                {
                    "exact_snippets": "History of exposure to cumulative anthracycline doses greater than",
                    "criterion": "cumulative anthracycline doses",
                    "requirements": [
                        {
                            "requirement_type": "exposure",
                            "expected_value": {
                                "operator": ">",
                                "value": 0,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Adriamycin > 400 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Adriamycin > 400 mg/m2",
                    "criterion": "Adriamycin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 400,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Epirubicin > 720 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Epirubicin > 720 mg/m2",
                    "criterion": "Epirubicin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 720,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Mitoxantrone > 120 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Mitoxantrone > 120 mg/m2",
                    "criterion": "Mitoxantrone dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 120,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Idarubicin > 90 mg/m2",
            "criterions": [
                {
                    "exact_snippets": "Idarubicin > 90 mg/m2",
                    "criterion": "Idarubicin dosage",
                    "requirements": [
                        {
                            "requirement_type": "dosage",
                            "expected_value": {
                                "operator": ">",
                                "value": 90,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.",
            "criterions": [
                {
                    "exact_snippets": "If another anthracycline or more than one anthracycline has been used",
                    "criterion": "anthracycline usage",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin",
                    "criterion": "cumulative dose of anthracycline",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 400,
                                "unit": "mg/m2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Cardiopulmonary dysfunction, defined as:",
            "criterions": [
                {
                    "exact_snippets": "Cardiopulmonary dysfunction",
                    "criterion": "cardiopulmonary dysfunction",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment.",
            "criterions": [
                {
                    "exact_snippets": "Uncontrolled hypertension",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "systolic > 150 mmHg",
                    "criterion": "systolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 150,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "diastolic > 100 mmHg",
                    "criterion": "diastolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 100,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "despite optimum medical treatment",
                    "criterion": "medical treatment",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": "optimum"
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.",
            "criterions": [
                {
                    "exact_snippets": "Angina pectoris ... poorly controlled with optimum medical treatment",
                    "criterion": "angina pectoris",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "poorly controlled with optimum medical treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "arrhythmia poorly controlled with optimum medical treatment",
                    "criterion": "arrhythmia",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "poorly controlled with optimum medical treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. History of congestive heart failure NCI CTCAE version 5.0 grade ≥ 3 NYHA class ≥ 2.",
            "criterions": [
                {
                    "exact_snippets": "History of congestive heart failure",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "NCI CTCAE version 5.0 grade ≥ 3",
                    "criterion": "NCI CTCAE grade for congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "NYHA class ≥ 2",
                    "criterion": "NYHA class for congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "class"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab.",
            "criterions": [
                {
                    "exact_snippets": "History of LVEF decrease to < 40%",
                    "criterion": "LVEF decrease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<",
                                "value": 40,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "symptomatic congestive heart failure during prior treatment with trastuzumab",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "trastuzumab"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Myocardial infarction within 6 months before randomization.",
            "criterions": [
                {
                    "exact_snippets": "Myocardial infarction within 6 months before randomization.",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<",
                                        "value": 6,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Resting dyspnea due to complications of the malignant disease, requiring continuous oxygen therapy.",
            "criterions": [
                {
                    "exact_snippets": "Resting dyspnea due to complications of the malignant disease",
                    "criterion": "resting dyspnea",
                    "requirements": [
                        {
                            "requirement_type": "cause",
                            "expected_value": "complications of the malignant disease"
                        }
                    ]
                },
                {
                    "exact_snippets": "requiring continuous oxygen therapy",
                    "criterion": "oxygen therapy",
                    "requirements": [
                        {
                            "requirement_type": "necessity",
                            "expected_value": "continuous"
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or hematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).",
            "criterions": [
                {
                    "exact_snippets": "severe, uncontrolled disease (pulmonary",
                    "criterion": "pulmonary disease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... cardiac",
                    "criterion": "cardiac disease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... metabolic",
                    "criterion": "metabolic disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... hematological disorder",
                    "criterion": "hematological disorder",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... wound healing disorders",
                    "criterion": "wound healing disorders",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... ulcers",
                    "criterion": "ulcers",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... bone fractures",
                    "criterion": "bone fractures",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe, uncontrolled disease ... infectious processes",
                    "criterion": "infectious processes",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Major surgery in the 28 days prior to randomization or foreseeable during study treatment period.",
            "criterions": [
                {
                    "exact_snippets": "Major surgery in the 28 days prior to randomization",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "in the 28 days prior to randomization"
                        }
                    ]
                },
                {
                    "exact_snippets": "foreseeable during study treatment period",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "foreseeable during study treatment period"
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Infection with HIV or active Hepatitis B and/or Hepatitis C.",
            "criterions": [
                {
                    "exact_snippets": "Infection with HIV",
                    "criterion": "HIV infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "active Hepatitis B",
                    "criterion": "active Hepatitis B",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "active ... Hepatitis C",
                    "criterion": "active Hepatitis C",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.",
            "criterions": [
                {
                    "exact_snippets": "History of trastuzumab intolerance",
                    "criterion": "trastuzumab intolerance",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "grade 3-4 infusion reaction",
                    "criterion": "infusion reaction",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 3,
                                        "unit": "grade"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 4,
                                        "unit": "grade"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity",
                    "criterion": "hypersensitivity",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Known hypersensitivity to any of the study drugs, including inactive ingredients.",
            "criterions": [
                {
                    "exact_snippets": "Known hypersensitivity to any of the study drugs",
                    "criterion": "hypersensitivity to study drugs",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "hypersensitivity to ... inactive ingredients",
                    "criterion": "hypersensitivity to inactive ingredients",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.",
            "criterions": [
                {
                    "exact_snippets": "Inability, in the opinion of the investigator, to comply with the protocol requirements",
                    "criterion": "ability to comply with protocol requirements",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder study follow-up",
                    "criterion": "comorbidity hindering study follow-up",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder ... response evaluation",
                    "criterion": "comorbidity hindering response evaluation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "any comorbidity that might hinder ... the informed consent process",
                    "criterion": "comorbidity hindering informed consent process",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "In cohort C, patients that are initially allocated in the control arm (physician's treatment choice) and have a documented disease progression can be re-randomized to receive the experimental or control treatment (if they meet the inclusion criteria after progression).",
            "criterions": [
                {
                    "exact_snippets": "patients that are initially allocated in the control arm",
                    "criterion": "initial allocation",
                    "requirements": [
                        {
                            "requirement_type": "allocation",
                            "expected_value": "control arm"
                        }
                    ]
                },
                {
                    "exact_snippets": "have a documented disease progression",
                    "criterion": "disease progression",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": true
                        }
                    ]
                }
            ]
        }
    ],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": [
        {
            "line": "Inclusion Criteria",
            "criterions": []
        },
        {
            "line": "For cohorts C:",
            "criterions": []
        },
        {
            "line": "Exclusion criteria",
            "criterions": []
        }
    ]
}