{
    "info": {
        "nct_id": "NCT03430882",
        "official_title": "A Phase I Study of TAK-228 (MLN0128) in Combination With Carboplatin Plus Paclitaxel in Patients With Advanced Malignancies",
        "inclusion_criteria": "* Patients must have a diagnosis of a solid tumor malignancy and is refractory to standard therapies who have relapsed after standard therapy, or whose cancers have no standard therapy.\n* Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status =< 1.\n* Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are of childbearing potential, agree to practice 1 effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling [e.g., United Surgical Partners International (USPI), summary of product characteristics (SmPC), etc,]) after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)\n* Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.\n* Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.\n* Platelet count >= 100 x 10^9/L.\n* Hemoglobin >= 9 g/dL without transfusion within 1 week preceding study drug administration.\n* Total bilirubin =< 1.5 x upper limit of normal (ULN).\n* Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) =< 2.5 x ULN (=< 5 x ULN if liver metastases are present).\n* Creatinine clearance >= 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour).\n* Glycosylated hemoglobin (HbA1c) < 7%.\n* Fasting serum glucose =< 130 mg/dL.\n* Fasting triglycerides =< 300 mg/dL.\n* Ability to swallow oral medications.\n* Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.\n* Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: a) Brain metastases which have been treated b) No evidence of disease progression for >= 3 months before the first dose of study drug. c) No hemorrhage after treatment d) Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228 e) No ongoing requirement for dexamethasone or anti-epileptic drugs.\n* Patients must have evaluable or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.\n* Patients must be 4 weeks beyond previous treatment of any chemotherapy or radiotherapy, and must have recovered to =< grade 1 or previous baseline for each toxicity. Exception: Patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field. Patients who have received non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4 weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic biological agents.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "* Carboplatin or paclitaxel exposure within past 6 months.\n* Central nervous system (CNS) metastasis.\n* Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.\n* Known history of human immunodeficiency virus infection.\n* Known history of hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.\n* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.\n* Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.\n* Breast feeding or pregnant.\n* Treatment with any investigational products within 4 weeks before the first dose of study drug.\n* Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors.\n* Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.\n* History of any of the following within the last 6 months before administration of the first dose of the drug: a) Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures b) Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures c) Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) d) Placement of a pacemaker for control of rhythm e) New York Heart Association (NYHA) class III or IV heart failure f) Pulmonary embolism.\n* Significant active cardiovascular or pulmonary disease including: a) Uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90 mm Hg). Use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed. b) Pulmonary hypertension c) Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air d) Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement e) Medically significant (symptomatic) bradycardia f) History of arrhythmia requiring an implantable cardiac defibrillator g) Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes).\n* Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.\n* Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.\n* Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.\n* Patients with hypersensitivity or other allergic reaction to platinum chemotherapy.\n* Patients with hypersensitivity or other allergic reaction to taxanes.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* Patients must have a diagnosis of a solid tumor malignancy and is refractory to standard therapies who have relapsed after standard therapy, or whose cancers have no standard therapy.",
            "criterions": [
                {
                    "exact_snippets": "diagnosis of a solid tumor malignancy",
                    "criterion": "solid tumor malignancy",
                    "requirements": [
                        {
                            "requirement_type": "diagnosis",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "refractory to standard therapies",
                    "criterion": "refractory to standard therapies",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "refractory"
                        }
                    ]
                },
                {
                    "exact_snippets": "relapsed after standard therapy",
                    "criterion": "relapse after standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "relapsed"
                        }
                    ]
                },
                {
                    "exact_snippets": "cancers have no standard therapy",
                    "criterion": "no standard therapy available",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status =< 1.",
            "criterions": [
                {
                    "exact_snippets": "Eastern Cooperative Oncology Group (ECOG) performance status ... =< 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "other performance status =< 1",
                    "criterion": "other performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are of childbearing potential, agree to practice 1 effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling [e.g., United Surgical Partners International (USPI), summary of product characteristics (SmPC), etc,]) after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)",
            "criterions": [
                {
                    "exact_snippets": "Female patients who: Are postmenopausal for at least 1 year before the screening visit",
                    "criterion": "menopausal status",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "year"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Female patients who: ... are surgically sterile",
                    "criterion": "surgical sterility",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Female patients who: ... if they are of childbearing potential, agree to practice 1 effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling ... after the last dose of study drug",
                    "criterion": "contraception use",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "1 effective method of contraception",
                                "1 additional effective (barrier) method"
                            ]
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 90,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Female patients who: ... agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient",
                    "criterion": "abstinence",
                    "requirements": [
                        {
                            "requirement_type": "practice",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Male patients",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": "male"
                        }
                    ]
                },
                {
                    "exact_snippets": "agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug",
                    "criterion": "contraception method",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "highly effective barrier contraception"
                        }
                    ]
                },
                {
                    "exact_snippets": "agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient",
                    "criterion": "contraception method",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "true abstinence"
                        }
                    ]
                },
                {
                    "exact_snippets": "Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug",
                    "criterion": "sperm donation",
                    "requirements": [
                        {
                            "requirement_type": "activity restriction",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) >= 1.5 x 10^9/L",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelet count >= 100 x 10^9/L.",
            "criterions": [
                {
                    "exact_snippets": "Platelet count >= 100 x 10^9/L",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 100,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Hemoglobin >= 9 g/dL without transfusion within 1 week preceding study drug administration.",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin >= 9 g/dL",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "without transfusion within 1 week preceding study drug administration",
                    "criterion": "transfusion",
                    "requirements": [
                        {
                            "requirement_type": "absence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "1 week preceding study drug administration"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Total bilirubin =< 1.5 x upper limit of normal (ULN).",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin =< 1.5 x upper limit of normal (ULN).",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) =< 2.5 x ULN (=< 5 x ULN if liver metastases are present).",
            "criterions": [
                {
                    "exact_snippets": "Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) =< 2.5 x ULN",
                    "criterion": "transaminases (AST/SGOT and ALT/SGPT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2.5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Transaminases ... =< 5 x ULN if liver metastases are present",
                    "criterion": "transaminases (AST/SGOT and ALT/SGPT) with liver metastases",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 5,
                                        "unit": "x ULN"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Creatinine clearance >= 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour).",
            "criterions": [
                {
                    "exact_snippets": "Creatinine clearance >= 50 mL/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "mL/min"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "based either on Cockcroft-Gault estimate",
                    "criterion": "creatinine clearance estimation method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "Cockcroft-Gault estimate"
                        }
                    ]
                },
                {
                    "exact_snippets": "based on urine collection (12 or 24 hour)",
                    "criterion": "creatinine clearance estimation method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "urine collection (12 hour)",
                                "urine collection (24 hour)"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Glycosylated hemoglobin (HbA1c) < 7%.",
            "criterions": [
                {
                    "exact_snippets": "Glycosylated hemoglobin (HbA1c) < 7%",
                    "criterion": "glycosylated hemoglobin (HbA1c)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<",
                                "value": 7,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Fasting serum glucose =< 130 mg/dL.",
            "criterions": [
                {
                    "exact_snippets": "Fasting serum glucose =< 130 mg/dL",
                    "criterion": "fasting serum glucose",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 130,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Fasting triglycerides =< 300 mg/dL.",
            "criterions": [
                {
                    "exact_snippets": "Fasting triglycerides =< 300 mg/dL.",
                    "criterion": "fasting triglycerides",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 300,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Ability to swallow oral medications.",
            "criterions": [
                {
                    "exact_snippets": "Ability to swallow oral medications.",
                    "criterion": "ability to swallow oral medications",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.",
            "criterions": [
                {
                    "exact_snippets": "Voluntary written consent must be given",
                    "criterion": "voluntary written consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: a) Brain metastases which have been treated b) No evidence of disease progression for >= 3 months before the first dose of study drug. c) No hemorrhage after treatment d) Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228 e) No ongoing requirement for dexamethasone or anti-epileptic drugs.",
            "criterions": [
                {
                    "exact_snippets": "history of brain metastasis",
                    "criterion": "history of brain metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Brain metastases which have been treated",
                    "criterion": "treatment of brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "completion",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "No evidence of disease progression for >= 3 months",
                    "criterion": "disease progression",
                    "requirements": [
                        {
                            "requirement_type": "progression",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "No hemorrhage after treatment",
                    "criterion": "hemorrhage after treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Off-treatment with dexamethasone for 4 weeks",
                    "criterion": "dexamethasone treatment",
                    "requirements": [
                        {
                            "requirement_type": "off-treatment duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "No ongoing requirement for dexamethasone or anti-epileptic drugs",
                    "criterion": "requirement for dexamethasone or anti-epileptic drugs",
                    "requirements": [
                        {
                            "requirement_type": "requirement",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have evaluable or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.",
            "criterions": [
                {
                    "exact_snippets": "evaluable or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria",
                    "criterion": "disease status",
                    "requirements": [
                        {
                            "requirement_type": "evaluation",
                            "expected_value": [
                                "evaluable",
                                "measurable"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must be 4 weeks beyond previous treatment of any chemotherapy or radiotherapy, and must have recovered to =< grade 1 or previous baseline for each toxicity. Exception: Patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field. Patients who have received non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4 weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic biological agents.",
            "criterions": [
                {
                    "exact_snippets": "Patients must be 4 weeks beyond previous treatment of any chemotherapy or radiotherapy",
                    "criterion": "time since last chemotherapy or radiotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 4,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "must have recovered to =< grade 1 or previous baseline for each toxicity",
                    "criterion": "recovery from treatment toxicity",
                    "requirements": [
                        {
                            "requirement_type": "toxicity grade",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 1,
                                        "unit": "grade"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field",
                    "criterion": "palliative low dose radiotherapy to the limbs",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 1,
                                        "unit": "weeks"
                                    },
                                    {
                                        "operator": "<=",
                                        "value": 4,
                                        "unit": "weeks"
                                    }
                                ]
                            }
                        },
                        {
                            "requirement_type": "radiotherapy field exclusion",
                            "expected_value": [
                                "pelvis",
                                "sternum",
                                "scapulae",
                                "vertebrae",
                                "skull"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients who have received non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4 weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic biological agents",
                    "criterion": "time since last non-chemotherapeutic biological agents",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": "at least 5 half-lives or 4 weeks, whichever is shorter"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "* Carboplatin or paclitaxel exposure within past 6 months.",
            "criterions": [
                {
                    "exact_snippets": "Carboplatin ... exposure within past 6 months.",
                    "criterion": "Carboplatin exposure",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "paclitaxel exposure within past 6 months.",
                    "criterion": "paclitaxel exposure",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Central nervous system (CNS) metastasis.",
            "criterions": [
                {
                    "exact_snippets": "Central nervous system (CNS) metastasis",
                    "criterion": "CNS metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.",
            "criterions": [
                {
                    "exact_snippets": "clinically significant co-morbidities",
                    "criterion": "clinically significant co-morbidities",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled pulmonary disease",
                    "criterion": "uncontrolled pulmonary disease",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "active central nervous system disease",
                    "criterion": "active central nervous system disease",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "active infection",
                    "criterion": "active infection",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "any other condition that could compromise the patient's participation in the study",
                    "criterion": "condition compromising study participation",
                    "requirements": [
                        {
                            "requirement_type": "potential to compromise participation",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Known history of human immunodeficiency virus infection.",
            "criterions": [
                {
                    "exact_snippets": "Known history of human immunodeficiency virus infection",
                    "criterion": "human immunodeficiency virus infection",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Known history of hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.",
            "criterions": [
                {
                    "exact_snippets": "Known history of hepatitis B surface antigen-positive",
                    "criterion": "hepatitis B surface antigen",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "known or suspected active hepatitis C infection",
                    "criterion": "active hepatitis C infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.",
            "criterions": [
                {
                    "exact_snippets": "serious medical ... illness",
                    "criterion": "serious medical illness",
                    "requirements": [
                        {
                            "requirement_type": "potential interference with treatment completion",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "serious ... psychiatric illness",
                    "criterion": "serious psychiatric illness",
                    "requirements": [
                        {
                            "requirement_type": "potential interference with treatment completion",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.",
            "criterions": [
                {
                    "exact_snippets": "Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug",
                    "criterion": "another malignancy",
                    "requirements": [
                        {
                            "requirement_type": "diagnosis or treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 2,
                                        "unit": "years"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "previously diagnosed with another malignancy and have any evidence of residual disease",
                    "criterion": "residual disease from another malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection",
                    "criterion": "non-melanoma skin cancer or carcinoma in situ",
                    "requirements": [
                        {
                            "requirement_type": "resection",
                            "expected_value": "complete"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Breast feeding or pregnant.",
            "criterions": [
                {
                    "exact_snippets": "Breast feeding",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "pregnant",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Treatment with any investigational products within 4 weeks before the first dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Treatment with any investigational products within 4 weeks before the first dose of study drug.",
                    "criterion": "treatment with investigational products",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": ">=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors.",
            "criterions": [
                {
                    "exact_snippets": "Previous treatment with dual PI3K/mTOR inhibitors",
                    "criterion": "previous treatment with dual PI3K/mTOR inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous treatment with ... TORC1/2 inhibitors",
                    "criterion": "previous treatment with TORC1/2 inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous treatment with ... TORC1 inhibitors",
                    "criterion": "previous treatment with TORC1 inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.",
            "criterions": [
                {
                    "exact_snippets": "Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason",
                    "criterion": "malabsorption",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with enteric stomata are also excluded",
                    "criterion": "enteric stomata",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of any of the following within the last 6 months before administration of the first dose of the drug: a) Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures b) Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures c) Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) d) Placement of a pacemaker for control of rhythm e) New York Heart Association (NYHA) class III or IV heart failure f) Pulmonary embolism.",
            "criterions": [
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... Ischemic myocardial event",
                    "criterion": "ischemic myocardial event",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... angina requiring therapy",
                    "criterion": "angina requiring therapy",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... artery revascularization procedures",
                    "criterion": "artery revascularization procedures",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... Ischemic cerebrovascular event",
                    "criterion": "ischemic cerebrovascular event",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... transient ischemic attack",
                    "criterion": "transient ischemic attack",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... artery revascularization procedures",
                    "criterion": "artery revascularization procedures",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... Requirement for inotropic support (excluding digoxin)",
                    "criterion": "requirement for inotropic support",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... serious (uncontrolled) cardiac arrhythmia",
                    "criterion": "serious (uncontrolled) cardiac arrhythmia",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... atrial flutter/fibrillation",
                    "criterion": "atrial flutter/fibrillation",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... ventricular fibrillation",
                    "criterion": "ventricular fibrillation",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... ventricular tachycardia",
                    "criterion": "ventricular tachycardia",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... Placement of a pacemaker for control of rhythm",
                    "criterion": "placement of a pacemaker for control of rhythm",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... New York Heart Association (NYHA) class III or IV heart failure",
                    "criterion": "New York Heart Association (NYHA) class III or IV heart failure",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of any of the following within the last 6 months ... Pulmonary embolism",
                    "criterion": "pulmonary embolism",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within the last 6 months"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Significant active cardiovascular or pulmonary disease including: a) Uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90 mm Hg). Use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed. b) Pulmonary hypertension c) Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air d) Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement e) Medically significant (symptomatic) bradycardia f) History of arrhythmia requiring an implantable cardiac defibrillator g) Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes).",
            "criterions": [
                {
                    "exact_snippets": "Significant active cardiovascular or pulmonary disease",
                    "criterion": "cardiovascular or pulmonary disease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "significant active"
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90 mm Hg)",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        },
                        {
                            "requirement_type": "systolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 150,
                                "unit": "mm Hg"
                            }
                        },
                        {
                            "requirement_type": "diastolic blood pressure",
                            "expected_value": {
                                "operator": ">",
                                "value": 90,
                                "unit": "mm Hg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Pulmonary hypertension",
                    "criterion": "pulmonary hypertension",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air",
                    "criterion": "asthma",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air",
                    "criterion": "oxygen saturation",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<",
                                "value": 90,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement",
                    "criterion": "valvular disease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "significant"
                        },
                        {
                            "requirement_type": "condition",
                            "expected_value": [
                                "severe regurgitation",
                                "stenosis"
                            ]
                        },
                        {
                            "requirement_type": "history",
                            "expected_value": "valve replacement"
                        }
                    ]
                },
                {
                    "exact_snippets": "Medically significant (symptomatic) bradycardia",
                    "criterion": "bradycardia",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "medically significant"
                        },
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "symptomatic"
                        }
                    ]
                },
                {
                    "exact_snippets": "History of arrhythmia requiring an implantable cardiac defibrillator",
                    "criterion": "arrhythmia",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "implantable cardiac defibrillator"
                        }
                    ]
                },
                {
                    "exact_snippets": "Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)",
                    "criterion": "QT interval prolongation",
                    "requirements": [
                        {
                            "requirement_type": "baseline",
                            "expected_value": "prolongation"
                        },
                        {
                            "requirement_type": "QTc interval",
                            "expected_value": {
                                "operator": ">",
                                "value": 480,
                                "unit": "milliseconds"
                            }
                        },
                        {
                            "requirement_type": "history",
                            "expected_value": [
                                "congenital long QT syndrome",
                                "torsades de pointes"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.",
            "criterions": [
                {
                    "exact_snippets": "Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%",
                    "criterion": "glycosylated hemoglobin (HbA1c)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">",
                                "value": 7,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with a history of transient glucose intolerance due to corticosteroid administration",
                    "criterion": "history of transient glucose intolerance due to corticosteroid administration",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.",
                    "criterion": "systemic corticosteroids",
                    "requirements": [
                        {
                            "requirement_type": "administration",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within 1 week before administration of the first dose of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Daily or chronic use of a proton pump inhibitor (PPI)",
                    "criterion": "proton pump inhibitor (PPI) use",
                    "requirements": [
                        {
                            "requirement_type": "frequency",
                            "expected_value": "daily or chronic"
                        }
                    ]
                },
                {
                    "exact_snippets": "having taken a PPI within 7 days before receiving the first dose of study drug",
                    "criterion": "proton pump inhibitor (PPI) use",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 7 days before receiving the first dose of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with hypersensitivity or other allergic reaction to platinum chemotherapy.",
            "criterions": [
                {
                    "exact_snippets": "hypersensitivity or other allergic reaction to platinum chemotherapy",
                    "criterion": "hypersensitivity or allergic reaction to platinum chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with hypersensitivity or other allergic reaction to taxanes.",
            "criterions": [
                {
                    "exact_snippets": "hypersensitivity or other allergic reaction to taxanes",
                    "criterion": "hypersensitivity or allergic reaction to taxanes",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": []
}