{
    "info": {
        "nct_id": "NCT03365882",
        "official_title": "S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification",
        "inclusion_criteria": "* STEP 1 INITIAL REGISTRATION: HER2 TESTING\n* Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable\n* Mutation results:\n\n  * All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible\n* Patients must not have been treated with any of the following prior to step 1 initial registration:\n\n  * Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR\n  * HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible\n* Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab\n* Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization\n* Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form\n* As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system\n* STEP 2 RANDOMIZATION\n* Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0)\n* Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form\n* Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible\n* Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization\n* Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization\n* Patients must have a Zubrod performance status of 0 or 1\n* Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization\n* Absolute neutrophil count (ANC) >= 1,500/mcL\n* Platelets >= 75,000/mcL\n* Hemoglobin >= 9 g/dL\n* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN)\n* Bilirubin =< 1.5 mg/dL\n* Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization\n* Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution\n* Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization\n* Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs\n* Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type\n* No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible\n* Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of \"reproductive potential\" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, \"effective contraception\" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures\n* Patients must be given the opportunity to consent to the optional submission of tissue for future research\n* Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form\n* STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN)\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form\n* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* STEP 1 INITIAL REGISTRATION: HER2 TESTING",
            "criterions": [
                {
                    "exact_snippets": "HER2 TESTING",
                    "criterion": "HER2",
                    "requirements": [
                        {
                            "requirement_type": "testing",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable",
            "criterions": [
                {
                    "exact_snippets": "histologically or cytologically documented adenocarcinoma of the colon or rectum",
                    "criterion": "adenocarcinoma of the colon or rectum",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": [
                                "histologically",
                                "cytologically"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic or locally advanced",
                    "criterion": "adenocarcinoma stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": [
                                "metastatic",
                                "locally advanced"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "unresectable",
                    "criterion": "resectability",
                    "requirements": [
                        {
                            "requirement_type": "resectability",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Mutation results:",
            "criterions": [
                {
                    "exact_snippets": "Mutation results",
                    "criterion": "mutation results",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible",
            "criterions": [
                {
                    "exact_snippets": "molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab",
                    "criterion": "molecular testing",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": "Clinical Laboratory Improvement Act (CLIA) certified lab"
                        }
                    ]
                },
                {
                    "exact_snippets": "KRAS and NRAS gene",
                    "criterion": "KRAS/NRAS gene",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "exon 15 of BRAF gene (BRAF V600E mutation)",
                    "criterion": "BRAF gene exon 15",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes",
                    "criterion": "activating mutation in KRAS/NRAS genes",
                    "requirements": [
                        {
                            "requirement_type": "mutation location",
                            "expected_value": [
                                "exon 2 [codons 12 and 13]",
                                "exon 3 [codons 59 and 61]",
                                "exon 4 [codons 117 and 146]"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "activating mutation ... exon 15 (BRAFV600E mutation) of BRAF gene",
                    "criterion": "activating mutation in BRAF gene",
                    "requirements": [
                        {
                            "requirement_type": "mutation location",
                            "expected_value": "exon 15 (BRAFV600E mutation)"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not have been treated with any of the following prior to step 1 initial registration:",
            "criterions": [
                {
                    "exact_snippets": "Patients must not have been treated with any of the following",
                    "criterion": "prior treatments",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR",
            "criterions": [
                {
                    "exact_snippets": "Cetuximab, panitumumab, or any other monoclonal antibody against EGFR",
                    "criterion": "monoclonal antibody against EGFR",
                    "requirements": [
                        {
                            "requirement_type": "exposure",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "inhibitor of EGFR",
                    "criterion": "EGFR inhibitor",
                    "requirements": [
                        {
                            "requirement_type": "exposure",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible",
            "criterions": [
                {
                    "exact_snippets": "HER-2 targeting for treatment of colorectal cancer",
                    "criterion": "HER-2 targeting",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": "colorectal cancer"
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who have received prior trastuzumab or pertuzumab",
                    "criterion": "prior trastuzumab or pertuzumab",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior history of adjuvant or neoadjuvant breast cancer treatment",
                    "criterion": "prior history of breast cancer treatment",
                    "requirements": [
                        {
                            "requirement_type": "treatment type",
                            "expected_value": [
                                "adjuvant",
                                "neoadjuvant"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer",
                    "criterion": "development of advanced colorectal cancer",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "after breast cancer treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab",
            "criterions": [
                {
                    "exact_snippets": "history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug",
                    "criterion": "toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab",
                    "criterion": "infusion-related reaction during prior therapy with pertuzumab or trastuzumab",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "tumor slides available for submission",
                    "criterion": "tumor slides",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HER-2 testing must be completed by the central lab",
                    "criterion": "HER-2 testing",
                    "requirements": [
                        {
                            "requirement_type": "completion",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "location",
                            "expected_value": "central lab"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form",
            "criterions": [
                {
                    "exact_snippets": "Patients must be informed of the investigational nature of this study",
                    "criterion": "patient information",
                    "requirements": [
                        {
                            "requirement_type": "awareness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "must sign and give informed consent",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "signed",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in accordance with institutional and federal guidelines",
                    "criterion": "guideline compliance",
                    "requirements": [
                        {
                            "requirement_type": "compliance",
                            "expected_value": [
                                "institutional",
                                "federal"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "for step 1 initial registration, the appropriate consent form is the step 1 consent form",
                    "criterion": "consent form",
                    "requirements": [
                        {
                            "requirement_type": "specific form",
                            "expected_value": "step 1 consent form"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system",
            "criterions": [
                {
                    "exact_snippets": "the current (within 365 days) date of institutional review board approval",
                    "criterion": "institutional review board approval date",
                    "requirements": [
                        {
                            "requirement_type": "recency",
                            "expected_value": {
                                "operator": "<=",
                                "value": 365,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 2 RANDOMIZATION",
            "criterions": [
                {
                    "exact_snippets": "STEP 2 RANDOMIZATION",
                    "criterion": "randomization",
                    "requirements": [
                        {
                            "requirement_type": "step",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0)",
            "criterions": [
                {
                    "exact_snippets": "HER-2 amplification as determined by central testing",
                    "criterion": "HER-2 amplification",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "3+ or 2+ by immunohistochemistry",
                    "criterion": "HER-2 immunohistochemistry score",
                    "requirements": [
                        {
                            "requirement_type": "score",
                            "expected_value": [
                                "3+",
                                "2+"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0",
                    "criterion": "HER-2 gene amplification ratio",
                    "requirements": [
                        {
                            "requirement_type": "ratio",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2.0,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form",
            "criterions": [
                {
                    "exact_snippets": "measurable disease",
                    "criterion": "disease measurability",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic or locally advanced and unresectable",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": [
                                "metastatic",
                                "locally advanced and unresectable"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "imaging used to assess all disease per RECIST 1.1",
                    "criterion": "disease assessment imaging",
                    "requirements": [
                        {
                            "requirement_type": "standard",
                            "expected_value": "RECIST 1.1"
                        }
                    ]
                },
                {
                    "exact_snippets": "imaging ... must have been completed within 28 days prior to step 2 randomization",
                    "criterion": "imaging timing",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "operator": "<=",
                                "value": 28,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "all disease must be assessed and documented on the Baseline Tumor Assessment Form",
                    "criterion": "disease documentation",
                    "requirements": [
                        {
                            "requirement_type": "form",
                            "expected_value": "Baseline Tumor Assessment Form"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible",
            "criterions": [
                {
                    "exact_snippets": "Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease",
                    "criterion": "prior systemic chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "regimen"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed following the most recent therapy",
                    "criterion": "progression following most recent therapy",
                    "requirements": [
                        {
                            "requirement_type": "progression",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior treatment with irinotecan is allowed",
                    "criterion": "prior treatment with irinotecan",
                    "requirements": [
                        {
                            "requirement_type": "allowance",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy",
                    "criterion": "adjuvant chemotherapy and disease recurrence",
                    "requirements": [
                        {
                            "requirement_type": "recurrence timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 6,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease",
                    "criterion": "adjuvant treatment and disease recurrence after 6 months",
                    "requirements": [
                        {
                            "requirement_type": "additional chemotherapy failure",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "line"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible",
                    "criterion": "lines of systemic chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<",
                                "value": 3,
                                "unit": "lines"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization",
                    "criterion": "prior therapy completion",
                    "requirements": [
                        {
                            "requirement_type": "time since completion",
                            "expected_value": {
                                "operator": ">=",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 ... prior to step 2 randomization",
                    "criterion": "toxicity resolution",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "CTCAE v4.0 grade 1"
                        }
                    ]
                },
                {
                    "exact_snippets": "(with the exception of CTCAE v4.0 grade 2 neuropathy)",
                    "criterion": "neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "CTCAE v4.0 grade 2"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "Brain metastases are allowed",
                    "criterion": "brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "adequately treated with radiotherapy or surgery",
                    "criterion": "treatment of brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": [
                                "radiotherapy",
                                "surgery"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "stable for at least 30 days prior to step 2 randomization",
                    "criterion": "stability of brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "duration of stability",
                            "expected_value": {
                                "operator": ">=",
                                "value": 30,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "neurologically asymptomatic",
                    "criterion": "neurological symptoms",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "without corticosteroid treatment for at least 7 days prior to step 2 randomization",
                    "criterion": "corticosteroid treatment",
                    "requirements": [
                        {
                            "requirement_type": "duration without treatment",
                            "expected_value": {
                                "operator": ">=",
                                "value": 7,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have a Zubrod performance status of 0 or 1",
            "criterions": [
                {
                    "exact_snippets": "Zubrod performance status of 0 or 1",
                    "criterion": "Zubrod performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "complete physical examination",
                    "criterion": "physical examination",
                    "requirements": [
                        {
                            "requirement_type": "completeness",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "medical history within 28 days",
                    "criterion": "medical history",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count (ANC) >= 1,500/mcL",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) >= 1,500/mcL",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelets >= 75,000/mcL",
            "criterions": [
                {
                    "exact_snippets": "Platelets >= 75,000/mcL",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 75000,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Hemoglobin >= 9 g/dL",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin >= 9 g/dL",
                    "criterion": "hemoglobin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN)",
            "criterions": [
                {
                    "exact_snippets": "Aspartate aminotransferase (AST) ... =< 5 x institutional upper limit of normal (IULN)",
                    "criterion": "aspartate aminotransferase (AST)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "x IULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alanine aminotransferase (ALT) ... =< 5 x institutional upper limit of normal (IULN)",
                    "criterion": "alanine aminotransferase (ALT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "x IULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Bilirubin =< 1.5 mg/dL",
            "criterions": [
                {
                    "exact_snippets": "Bilirubin =< 1.5 mg/dL",
                    "criterion": "bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "Calculated creatinine clearance > 30 ml/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 30,
                                "unit": "ml/min"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "within 14 days prior to step 2 randomization",
                    "criterion": "timeframe for creatinine clearance measurement",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 14 days prior to step 2 randomization"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution",
            "criterions": [
                {
                    "exact_snippets": "echocardiogram performed within 6 months prior to step 2 randomization",
                    "criterion": "echocardiogram",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 6 months prior to step 2 randomization"
                        }
                    ]
                },
                {
                    "exact_snippets": "ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution",
                    "criterion": "ventricular ejection fraction",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 50,
                                        "unit": "%"
                                    }
                                ]
                            }
                        },
                        {
                            "requirement_type": "value",
                            "expected_value": "within normal limits for the institution"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization",
            "criterions": [
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... diabetes",
                    "criterion": "uncontrolled diabetes",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... hypertension",
                    "criterion": "uncontrolled hypertension",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... severe infection",
                    "criterion": "severe infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... severe malnutrition",
                    "criterion": "severe malnutrition",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... unstable angina",
                    "criterion": "unstable angina",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... class III-IV New York Heart Association (NYHA) congestive heart failure",
                    "criterion": "class III-IV NYHA congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... ventricular arrhythmias",
                    "criterion": "ventricular arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... active ischemic heart disease",
                    "criterion": "active ischemic heart disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled intercurrent illness ... myocardial infarction within 6 months prior to step 2 randomization",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "operator": "<",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs",
            "criterions": [
                {
                    "exact_snippets": "known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions",
                    "criterion": "susceptibility to hypersensitivity or allergic reactions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies",
                    "criterion": "hypersensitivity to study treatments or excipients",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with mild or seasonal allergies may be included after discussion with the study chairs",
                    "criterion": "mild or seasonal allergies",
                    "requirements": [
                        {
                            "requirement_type": "inclusion",
                            "expected_value": "after discussion with the study chairs"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type",
            "criterions": [
                {
                    "exact_snippets": "Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy)",
                    "criterion": "treatment with other systemic anti-cancer agents",
                    "requirements": [
                        {
                            "requirement_type": "planning",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients must not be planning treatment with ... other treatments not part of protocol-specified anti-cancer therapy",
                    "criterion": "treatment with other treatments not part of protocol-specified anti-cancer therapy",
                    "requirements": [
                        {
                            "requirement_type": "planning",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients must not be planning treatment with ... concurrent investigational agents of any type",
                    "criterion": "treatment with concurrent investigational agents",
                    "requirements": [
                        {
                            "requirement_type": "planning",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible",
            "criterions": [
                {
                    "exact_snippets": "No prior malignancy is allowed",
                    "criterion": "prior malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "except for adequately treated basal cell or squamous cell skin cancer",
                    "criterion": "adequately treated basal cell or squamous cell skin cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... in situ cervical cancer",
                    "criterion": "in situ cervical cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... ductal carcinoma in situ",
                    "criterion": "ductal carcinoma in situ",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... other low grade lesions such as incidental appendix carcinoid",
                    "criterion": "other low grade lesions such as incidental appendix carcinoid",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "except for ... any other cancer from which the patient has been disease and treatment free for two years",
                    "criterion": "any other cancer",
                    "requirements": [
                        {
                            "requirement_type": "disease and treatment free duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "prostate cancer patients on active surveillance are eligible",
                    "criterion": "prostate cancer on active surveillance",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of \"reproductive potential\" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, \"effective contraception\" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures",
            "criterions": [
                {
                    "exact_snippets": "Patients must not be pregnant",
                    "criterion": "pregnancy status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "not be ... nursing",
                    "criterion": "nursing status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration",
                    "criterion": "serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 7 days prior to registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment",
                    "criterion": "contraceptive use",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": "while on study and for at least 7 months after the last dose of study treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "a woman is considered to be of \"reproductive potential\" if she has had menses at any time in the preceding 12 consecutive months",
                    "criterion": "reproductive potential",
                    "requirements": [
                        {
                            "requirement_type": "definition",
                            "expected_value": "has had menses at any time in the preceding 12 consecutive months"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must be given the opportunity to consent to the optional submission of tissue for future research",
            "criterions": [
                {
                    "exact_snippets": "optional submission of tissue for future research",
                    "criterion": "tissue submission for future research",
                    "requirements": [
                        {
                            "requirement_type": "consent opportunity",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form",
            "criterions": [
                {
                    "exact_snippets": "Patients must be informed of the investigational nature of this study",
                    "criterion": "patient information",
                    "requirements": [
                        {
                            "requirement_type": "awareness",
                            "expected_value": "investigational nature of this study"
                        }
                    ]
                },
                {
                    "exact_snippets": "must sign and give written informed consent",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "signed",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in accordance with institutional and federal guidelines",
                    "criterion": "guideline compliance",
                    "requirements": [
                        {
                            "requirement_type": "compliance",
                            "expected_value": [
                                "institutional guidelines",
                                "federal guidelines"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "the appropriate consent form for this registration is the step 2 consent form",
                    "criterion": "consent form type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": "step 2 consent form"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system",
            "criterions": [
                {
                    "exact_snippets": "treating institution's identity is provided",
                    "criterion": "treating institution's identity",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "current (within 365 days) date of institutional review board approval",
                    "criterion": "date of institutional review board approval",
                    "requirements": [
                        {
                            "requirement_type": "recency",
                            "expected_value": {
                                "operator": "<=",
                                "value": 365,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible",
            "criterions": [
                {
                    "exact_snippets": "documented disease progression while on CETIRI (Arm 2)",
                    "criterion": "disease progression on CETIRI",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG)",
                    "criterion": "submission of Follow-up Tumor Assessment Form",
                    "requirements": [
                        {
                            "requirement_type": "submission",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment",
                    "criterion": "registration timing",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "operator": "<=",
                                "value": 28,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1",
            "criterions": [
                {
                    "exact_snippets": "Zubrod performance status of 0 or 1",
                    "criterion": "Zubrod performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL",
            "criterions": [
                {
                    "exact_snippets": "ANC >= 1,500/mcL",
                    "criterion": "ANC (Absolute Neutrophil Count)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL",
            "criterions": [
                {
                    "exact_snippets": "Platelets >= 75,000/mcL",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 75000,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin >= 9 g/dL",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN)",
            "criterions": [
                {
                    "exact_snippets": "AST and ALT both =< 5 x institutional upper limit of normal (IULN)",
                    "criterion": "AST and ALT levels",
                    "requirements": [
                        {
                            "requirement_type": "comparison",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "x institutional upper limit of normal (IULN)"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL",
            "criterions": [
                {
                    "exact_snippets": "Bilirubin =< 1.5 mg/dL",
                    "criterion": "bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration",
            "criterions": [
                {
                    "exact_snippets": "Calculated creatinine clearance > 30 ml/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 30,
                                "unit": "ml/min"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "within 14 days prior to step 3 crossover registration",
                    "criterion": "timeframe for creatinine clearance measurement",
                    "requirements": [
                        {
                            "requirement_type": "timeframe",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration",
            "criterions": [
                {
                    "exact_snippets": "left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution",
                    "criterion": "left ventricular ejection fraction (LVEF)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 50,
                                        "unit": "%"
                                    },
                                    {
                                        "operator": ">=",
                                        "value": 0,
                                        "unit": "lower limit of normal for the institution"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "echocardiogram within 14 days prior to step 3 crossover registration",
                    "criterion": "echocardiogram",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration",
            "criterions": [
                {
                    "exact_snippets": "magnesium ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "magnesium test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "potassium ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "potassium test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "calcium ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "calcium test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "sodium ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "sodium test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "bicarbonate ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "bicarbonate test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                },
                {
                    "exact_snippets": "chloride ... performed within 14 days prior to step 3 crossover registration",
                    "criterion": "chloride test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days prior to step 3 crossover registration"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form",
            "criterions": [
                {
                    "exact_snippets": "Patients must be informed of the investigational nature of this study",
                    "criterion": "patient information",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "must sign and give written informed consent",
                    "criterion": "written informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in accordance with institutional and federal guidelines",
                    "criterion": "compliance with guidelines",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system",
            "criterions": [
                {
                    "exact_snippets": "the current (within 365 days) date of institutional review board approval",
                    "criterion": "institutional review board approval date",
                    "requirements": [
                        {
                            "requirement_type": "recency",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 365,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": []
}