{
    "info": {
        "nct_id": "NCT01973660",
        "official_title": "PAMELA: PAM50 HER2-enriched Phenotype as a Predictor of Early Response to Neoadjuvant Lapatinib Plus Trastuzumab in Stage I to IIIA HER2-positive Breast Cancer",
        "inclusion_criteria": "* Written informed consent prior to beginning specific protocol procedures\n* Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)\n* Histologically confirmed invasive breast carcinoma, with all of the following characteristics: primary tumor ≥1 cm in largest diameter, cN0-2, No evidence of distant metastasis (M0)\n* HER2-positive invasive breast cancer by central assessment, defined by ASCO/CAP guidelines\n* Female patients\n* Age ≥18 years\n* ECOG performance status of 0 or 1\n* Adequate organ function defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L, Hemoglobin (Hgb) ≥10 g/dL, Platelets >100 000/mm3, Creatinine ≤1.6 mg/dL, ALT and AST ≤2.5 × ULN, Alkaline phosphatase ≤5 ULN, Total bilirubin ≤1.5 mg/dL, Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan\n* Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product\n* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule\n* In the case of multifocal tumor (defined as the presence of two or more tumor foci in the same quadrant of the breast), the largest lesion must be ≥ 1 cm, and \"target lesion\" must be designated for all subsequent tumor assessments. In all tumor foci should be documented HER2 status as positive\n* Availability of enough tumor sample or possibility to take a new biopsy for PAM50 analysis\nHealthy volunteers allowed\nMust be FEMALE\nMust have minimum age of 18 Years",
        "exclusion_criteria": "* Stage III inoperable breast cancer or known metastatic disease\n* Patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment\n* Prior chemotherapy, radiotherapy or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy\n* Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years\n* Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances\n* Concurrent congestive heart failure or LVEF <50%\n* Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (<6 months before enrollment), unstable angina pectoris, myocardial infarction ≤6 months before enrollment, uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or high-risk uncontrolled arrhythmias\n* Uncontrolled diabetes mellitus, active peptic ulcer disease or uncontrolled epilepsy\n* Active uncontrolled infection at the time of enrollment\n* History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent\n* Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment\n* Patients who are pregnant or breast-feeding\n* Women of child-bearing potential who are unable or unwilling to use contraceptive measures\n* Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator\n* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded\n* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies)\n* Concomitant use of CYP3A4 inhibitors or inducers",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* Written informed consent prior to beginning specific protocol procedures",
            "criterions": [
                {
                    "exact_snippets": "Written informed consent",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)",
            "criterions": [
                {
                    "exact_snippets": "Untreated invasive breast carcinoma",
                    "criterion": "breast carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "untreated"
                        },
                        {
                            "requirement_type": "invasiveness",
                            "expected_value": "invasive"
                        }
                    ]
                },
                {
                    "exact_snippets": "eligible for primary definitive surgery",
                    "criterion": "surgery eligibility",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": "primary definitive surgery"
                        }
                    ]
                },
                {
                    "exact_snippets": "stage I-IIIA",
                    "criterion": "cancer stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 1,
                                        "unit": "stage"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 3,
                                        "unit": "stage"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Histologically confirmed invasive breast carcinoma, with all of the following characteristics: primary tumor ≥1 cm in largest diameter, cN0-2, No evidence of distant metastasis (M0)",
            "criterions": [
                {
                    "exact_snippets": "Histologically confirmed invasive breast carcinoma",
                    "criterion": "invasive breast carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": "histologically confirmed"
                        }
                    ]
                },
                {
                    "exact_snippets": "primary tumor ≥1 cm in largest diameter",
                    "criterion": "primary tumor size",
                    "requirements": [
                        {
                            "requirement_type": "size",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "cm"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "cN0-2",
                    "criterion": "clinical nodal status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": [
                                "cN0",
                                "cN1",
                                "cN2"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "No evidence of distant metastasis (M0)",
                    "criterion": "distant metastasis",
                    "requirements": [
                        {
                            "requirement_type": "evidence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* HER2-positive invasive breast cancer by central assessment, defined by ASCO/CAP guidelines",
            "criterions": [
                {
                    "exact_snippets": "HER2-positive invasive breast cancer",
                    "criterion": "HER2 status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "invasive breast cancer",
                    "criterion": "breast cancer type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "invasive"
                        }
                    ]
                },
                {
                    "exact_snippets": "by central assessment",
                    "criterion": "assessment method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "central assessment"
                        }
                    ]
                },
                {
                    "exact_snippets": "defined by ASCO/CAP guidelines",
                    "criterion": "guideline adherence",
                    "requirements": [
                        {
                            "requirement_type": "adherence",
                            "expected_value": "ASCO/CAP guidelines"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Female patients",
            "criterions": [
                {
                    "exact_snippets": "Female patients",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "expected gender",
                            "expected_value": "female"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Age ≥18 years",
            "criterions": [
                {
                    "exact_snippets": "Age ≥18 years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* ECOG performance status of 0 or 1",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status of 0 or 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Adequate organ function defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L, Hemoglobin (Hgb) ≥10 g/dL, Platelets >100 000/mm3, Creatinine ≤1.6 mg/dL, ALT and AST ≤2.5 × ULN, Alkaline phosphatase ≤5 ULN, Total bilirubin ≤1.5 mg/dL, Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) ≥1.5 × 109/L",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "× 109/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Hemoglobin (Hgb) ≥10 g/dL",
                    "criterion": "hemoglobin (Hgb)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 10,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Platelets >100 000/mm3",
                    "criterion": "platelets",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 100000,
                                "unit": "mm3"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Creatinine ≤1.6 mg/dL",
                    "criterion": "creatinine",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.6,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "ALT and AST ≤2.5 × ULN",
                    "criterion": "ALT and AST",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Alkaline phosphatase ≤5 ULN",
                    "criterion": "alkaline phosphatase",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Total bilirubin ≤1.5 mg/dL",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan",
                    "criterion": "baseline LVEF",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product",
            "criterions": [
                {
                    "exact_snippets": "Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity",
                    "criterion": "β-HCG pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                },
                {
                    "exact_snippets": "premenopausal women of reproductive capacity (those who are biologically capable of having children)",
                    "criterion": "premenopausal status",
                    "requirements": [
                        {
                            "requirement_type": "biological capability",
                            "expected_value": "capable of having children"
                        }
                    ]
                },
                {
                    "exact_snippets": "women less than 12 months after the menopause",
                    "criterion": "postmenopausal status",
                    "requirements": [
                        {
                            "requirement_type": "time since menopause",
                            "expected_value": {
                                "operator": "<",
                                "value": 12,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control",
                    "criterion": "birth control commitment",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product",
                    "criterion": "birth control duration",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": "2 weeks before first dose to 28 days after last dose"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule",
            "criterions": [
                {
                    "exact_snippets": "Absence of any psychological ... condition potentially hampering compliance",
                    "criterion": "psychological condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of any ... familial ... condition potentially hampering compliance",
                    "criterion": "familial condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of any ... sociological ... condition potentially hampering compliance",
                    "criterion": "sociological condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Absence of any ... geographical condition potentially hampering compliance",
                    "criterion": "geographical condition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* In the case of multifocal tumor (defined as the presence of two or more tumor foci in the same quadrant of the breast), the largest lesion must be ≥ 1 cm, and \"target lesion\" must be designated for all subsequent tumor assessments. In all tumor foci should be documented HER2 status as positive",
            "criterions": [
                {
                    "exact_snippets": "multifocal tumor (defined as the presence of two or more tumor foci in the same quadrant of the breast)",
                    "criterion": "multifocal tumor",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "largest lesion must be ≥ 1 cm",
                    "criterion": "largest lesion size",
                    "requirements": [
                        {
                            "requirement_type": "size",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "cm"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "\"target lesion\" must be designated for all subsequent tumor assessments",
                    "criterion": "target lesion designation",
                    "requirements": [
                        {
                            "requirement_type": "designation",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "In all tumor foci should be documented HER2 status as positive",
                    "criterion": "HER2 status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Availability of enough tumor sample or possibility to take a new biopsy for PAM50 analysis",
            "criterions": [
                {
                    "exact_snippets": "Availability of enough tumor sample",
                    "criterion": "tumor sample",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "quantity",
                            "expected_value": "enough"
                        }
                    ]
                },
                {
                    "exact_snippets": "possibility to take a new biopsy",
                    "criterion": "new biopsy",
                    "requirements": [
                        {
                            "requirement_type": "possibility",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "PAM50 analysis",
                    "criterion": "PAM50 analysis",
                    "requirements": [
                        {
                            "requirement_type": "purpose",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must be FEMALE",
            "criterions": [
                {
                    "exact_snippets": "Must be FEMALE",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": "FEMALE"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "* Stage III inoperable breast cancer or known metastatic disease",
            "criterions": [
                {
                    "exact_snippets": "Stage III inoperable breast cancer",
                    "criterion": "breast cancer",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "III"
                        },
                        {
                            "requirement_type": "operability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "known metastatic disease",
                    "criterion": "metastatic disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment",
            "criterions": [
                {
                    "exact_snippets": "upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate",
                    "criterion": "upfront chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "appropriateness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "optimal neoadjuvant treatment",
                    "criterion": "neoadjuvant treatment",
                    "requirements": [
                        {
                            "requirement_type": "optimal",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Prior chemotherapy, radiotherapy or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy",
            "criterions": [
                {
                    "exact_snippets": "Prior chemotherapy, radiotherapy or surgery for invasive breast cancer",
                    "criterion": "prior treatment for invasive breast cancer",
                    "requirements": [
                        {
                            "requirement_type": "treatment type",
                            "expected_value": [
                                "chemotherapy",
                                "radiotherapy",
                                "surgery"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "excision of tumor in the contralateral breast",
                    "criterion": "excision of tumor in the contralateral breast",
                    "requirements": [
                        {
                            "requirement_type": "procedure",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy",
                    "criterion": "prior adjuvant therapy",
                    "requirements": [
                        {
                            "requirement_type": "treatment type",
                            "expected_value": [
                                "radiotherapy",
                                "chemotherapy"
                            ]
                        },
                        {
                            "requirement_type": "previous receipt",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years",
            "criterions": [
                {
                    "exact_snippets": "concurrently active second malignancy",
                    "criterion": "second malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "adequately treated non-melanoma skin cancers",
                    "criterion": "non-melanoma skin cancers",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "adequately treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "in situ melanoma",
                    "criterion": "in situ melanoma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in situ cervical cancer",
                    "criterion": "in situ cervical cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "other non-mammary malignancies ... disease-free for at least 5 years",
                    "criterion": "non-mammary malignancies",
                    "requirements": [
                        {
                            "requirement_type": "disease-free duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 5,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances",
            "criterions": [
                {
                    "exact_snippets": "Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances",
                    "criterion": "hypersensitivity reaction",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Concurrent congestive heart failure or LVEF <50%",
            "criterions": [
                {
                    "exact_snippets": "Concurrent congestive heart failure",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "LVEF <50%",
                    "criterion": "left ventricular ejection fraction (LVEF)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (<6 months before enrollment), unstable angina pectoris, myocardial infarction ≤6 months before enrollment, uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or high-risk uncontrolled arrhythmias",
            "criterions": [
                {
                    "exact_snippets": "Clinically significant (i.e. active) cardiovascular disease",
                    "criterion": "cardiovascular disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "cerebrovascular accident (<6 months before enrollment)",
                    "criterion": "cerebrovascular accident",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "operator": "<",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "unstable angina pectoris",
                    "criterion": "unstable angina pectoris",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "myocardial infarction ≤6 months before enrollment",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg)",
                    "criterion": "uncontrolled hypertension",
                    "requirements": [
                        {
                            "requirement_type": "systolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 150,
                                "unit": "mmHg"
                            }
                        },
                        {
                            "requirement_type": "diastolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 100,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "high-risk uncontrolled arrhythmias",
                    "criterion": "uncontrolled arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "risk level",
                            "expected_value": "high-risk"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Uncontrolled diabetes mellitus, active peptic ulcer disease or uncontrolled epilepsy",
            "criterions": [
                {
                    "exact_snippets": "Uncontrolled diabetes mellitus",
                    "criterion": "diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "active peptic ulcer disease",
                    "criterion": "peptic ulcer disease",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled epilepsy",
                    "criterion": "epilepsy",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Active uncontrolled infection at the time of enrollment",
            "criterions": [
                {
                    "exact_snippets": "Active uncontrolled infection",
                    "criterion": "infection",
                    "requirements": [
                        {
                            "requirement_type": "control status",
                            "expected_value": "uncontrolled"
                        },
                        {
                            "requirement_type": "activity status",
                            "expected_value": "active"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent",
            "criterions": [
                {
                    "exact_snippets": "History of significant comorbidities",
                    "criterion": "significant comorbidities",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment",
            "criterions": [
                {
                    "exact_snippets": "Use of any investigational agent",
                    "criterion": "use of investigational agent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "participation in another therapeutic clinical trial concurrently",
                    "criterion": "participation in another therapeutic clinical trial",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "participation in another therapeutic clinical trial ... in the previous 30 days before the enrollment",
                    "criterion": "participation in another therapeutic clinical trial",
                    "requirements": [
                        {
                            "requirement_type": "time since last participation",
                            "expected_value": {
                                "operator": ">=",
                                "value": 30,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients who are pregnant or breast-feeding",
            "criterions": [
                {
                    "exact_snippets": "Patients who are pregnant",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "breast-feeding",
                    "criterion": "breast-feeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Women of child-bearing potential who are unable or unwilling to use contraceptive measures",
            "criterions": [
                {
                    "exact_snippets": "Women of child-bearing potential",
                    "criterion": "child-bearing potential",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unable or unwilling to use contraceptive measures",
                    "criterion": "use of contraceptive measures",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator",
            "criterions": [
                {
                    "exact_snippets": "Inability ... to abide by the study protocol",
                    "criterion": "ability to abide by the study protocol",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unwillingness to abide by the study protocol",
                    "criterion": "willingness to abide by the study protocol",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Inability ... to ... cooperate fully with the investigator",
                    "criterion": "ability to cooperate fully with the investigator",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unwillingness to ... cooperate fully with the investigator",
                    "criterion": "willingness to cooperate fully with the investigator",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded",
            "criterions": [
                {
                    "exact_snippets": "Malabsorption syndrome",
                    "criterion": "malabsorption syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "disease significantly affecting gastrointestinal function",
                    "criterion": "disease affecting gastrointestinal function",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "significant"
                        }
                    ]
                },
                {
                    "exact_snippets": "resection of the stomach or small bowel",
                    "criterion": "resection of the stomach or small bowel",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "ulcerative colitis",
                    "criterion": "ulcerative colitis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies)",
            "criterions": [
                {
                    "exact_snippets": "Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies)",
                    "criterion": "concurrent neoadjuvant cancer therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Concomitant use of CYP3A4 inhibitors or inducers",
            "criterions": [
                {
                    "exact_snippets": "Concomitant use of CYP3A4 inhibitors",
                    "criterion": "CYP3A4 inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "concomitant use",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Concomitant use of ... inducers",
                    "criterion": "CYP3A4 inducers",
                    "requirements": [
                        {
                            "requirement_type": "concomitant use",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": []
}