{
    "info": {
        "nct_id": "NCT03520491",
        "official_title": "A Pilot Study to Evaluate the Safety of Neoadjuvant Nivolumab Alone or in Combination With Ipilimumab for Cisplatin-Ineligible Patients With Muscle Invasive Bladder Cancer (CA209-9DJ)",
        "inclusion_criteria": "* Histologically confirmed diagnosis of urothelial carcinoma of the bladder. Variant histology is acceptable if there is a predominant urothelial component.\n* For MUSCLE-INVASIVE UROTHELIAL CANCER OF THE BLADDER (Cohorts 1 - 3):\n\n  ° Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease. Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.\n* For UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (URETER OR RENAL PELVIS) (Cohort U):\n\n  °Histologically confirmed high grade urothelial carcinoma of the upper tract and/or radiographically visible tumor stage T2-T4a N0/x M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. (Variant histology is acceptable if there is a predominant urothelial component)\n* Patients ineligible for cisplatin based on any of the following criteria:\n\n  * Estimated or calculated creatinine clearance ≥ 30ml/min but < 60 ml/min\n  * Grade 2 or above audiometric hearing loss (per CTCAE v4.0)\n  * Grade 2 or above peripheral neuropathy (per CTCAE v4.0)\n* Availability of tumor specimen block or 30 unstained slides from diagnosis of muscle-invasive disease. Patients with fewer than 30 slides available may be enrolled after discussion with the Principal Investigator.\n* Karnofsky performance status ≥ 70%.\n* Medically appropriate candidate for radical cystectomy, as per MSK Attending Urologic Oncologist\n* Age ≥ 18 years.\n* Required initial laboratory values:\n\n  * Absolute neutrophil count ≥ 1.5 x 10^9/L\n  * Platelets ≥ 100 x 10^9/L\n  * Bilirubin ≤1.5 times the upper limit of normal (x ULN)\n  * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN\n  * PTT/PT ≤1.5 x ULN or INR < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "* Prior treatment with systemic chemotherapy for urothelial cancer, including immune checkpoint inhibitors for non-muscle invasive bladder cancer. (Prior intravesical treatment such as BCG is allowed.)\n* Prior bladder-directed radiotherapy (exclusion applies only to MIBC Cohorts 1 - 3).\n* Presence of active autoimmune disease, symptoms, or conditions, with the following exceptions:\n\n  °Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, asymptomatic laboratory evidence of autoimmune disease (e.g.: +ANA, +RF, anti-thyroglobulin antibodies), or conditions not expected to recur in the absence of an external trigger are permitted to enroll.\n* Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.\n* Unstable angina.\n* New York Heart Association (NYHA) Grade II or greater congestive heart failure.\n* History of myocardial infarction within 6 months.\n* History of stroke within 6 months.\n* Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose.\n* Major surgical procedure within 28 days prior to the study. (Transurethral resection of bladder tumor is permitted\n* Serious, non-healing wound, ulcer, or bone fracture.\n* Other prior malignancy active within the previous 2 years except for local or organ-confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study.\n* Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other medicines specifically targeting T cells are prohibited. Prior IL-2 is permitted.\n* Prior therapy with intravesical BCG within 6 weeks of treatment.\n* Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection.\n* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).\n* History of allergy to study drug component or history of severe hypersensitivity reaction to any monoclonal antibody.\n* Women who are breastfeeding or pregnant as evidenced by a positive pregnancy test within 14 days of first dose.\n* Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover).\n* Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle).\n\n  * WOCBP are defined as those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post-menopausal is defined as:\n  * Amenorrhea ≥ 12 consecutive months without another cause, or\n  * For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL\n* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.\n* Inability to comply with study and/or follow-up procedures.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* Histologically confirmed diagnosis of urothelial carcinoma of the bladder. Variant histology is acceptable if there is a predominant urothelial component.",
            "criterions": [
                {
                    "exact_snippets": "Histologically confirmed diagnosis of urothelial carcinoma of the bladder.",
                    "criterion": "urothelial carcinoma of the bladder",
                    "requirements": [
                        {
                            "requirement_type": "diagnosis",
                            "expected_value": "histologically confirmed"
                        }
                    ]
                },
                {
                    "exact_snippets": "Variant histology is acceptable if there is a predominant urothelial component.",
                    "criterion": "variant histology",
                    "requirements": [
                        {
                            "requirement_type": "acceptability",
                            "expected_value": "predominant urothelial component"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* For MUSCLE-INVASIVE UROTHELIAL CANCER OF THE BLADDER (Cohorts 1 - 3):",
            "criterions": [
                {
                    "exact_snippets": "MUSCLE-INVASIVE UROTHELIAL CANCER OF THE BLADDER",
                    "criterion": "urothelial cancer of the bladder",
                    "requirements": [
                        {
                            "requirement_type": "invasiveness",
                            "expected_value": "muscle-invasive"
                        }
                    ]
                }
            ]
        },
        {
            "line": "° Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease. Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.",
            "criterions": [
                {
                    "exact_snippets": "Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "confirmation method",
                            "expected_value": [
                                "cystoscopic",
                                "radiographic"
                            ]
                        },
                        {
                            "requirement_type": "stage",
                            "expected_value": "cT2-4a cN0 cM0"
                        }
                    ]
                },
                {
                    "exact_snippets": "cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion",
                    "criterion": "cT4a disease invasion",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": "prostatic stroma"
                        },
                        {
                            "requirement_type": "cystoscopic confirmation of muscle invasion",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* For UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (URETER OR RENAL PELVIS) (Cohort U):",
            "criterions": [
                {
                    "exact_snippets": "UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (URETER OR RENAL PELVIS)",
                    "criterion": "urothelial carcinoma location",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "upper urinary tract",
                                "ureter",
                                "renal pelvis"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "°Histologically confirmed high grade urothelial carcinoma of the upper tract and/or radiographically visible tumor stage T2-T4a N0/x M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. (Variant histology is acceptable if there is a predominant urothelial component)",
            "criterions": [
                {
                    "exact_snippets": "Histologically confirmed high grade urothelial carcinoma",
                    "criterion": "urothelial carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": "histologically confirmed"
                        },
                        {
                            "requirement_type": "grade",
                            "expected_value": "high"
                        }
                    ]
                },
                {
                    "exact_snippets": "urothelial carcinoma of the upper tract",
                    "criterion": "urothelial carcinoma location",
                    "requirements": [
                        {
                            "requirement_type": "location",
                            "expected_value": "upper tract"
                        }
                    ]
                },
                {
                    "exact_snippets": "radiographically visible tumor stage T2-T4a N0/x M0 disease",
                    "criterion": "tumor stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": [
                                "T2",
                                "T3",
                                "T4a"
                            ]
                        },
                        {
                            "requirement_type": "node involvement",
                            "expected_value": "N0/x"
                        },
                        {
                            "requirement_type": "metastasis",
                            "expected_value": "M0"
                        }
                    ]
                },
                {
                    "exact_snippets": "positive selective urinary cytology",
                    "criterion": "urinary cytology",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "Hydronephrosis associated with tumor on imaging or biopsy",
                    "criterion": "hydronephrosis",
                    "requirements": [
                        {
                            "requirement_type": "association",
                            "expected_value": "associated with tumor on imaging or biopsy"
                        }
                    ]
                },
                {
                    "exact_snippets": "Variant histology is acceptable if there is a predominant urothelial component",
                    "criterion": "variant histology",
                    "requirements": [
                        {
                            "requirement_type": "acceptability",
                            "expected_value": "acceptable if predominant urothelial component"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients ineligible for cisplatin based on any of the following criteria:",
            "criterions": [
                {
                    "exact_snippets": "ineligible for cisplatin",
                    "criterion": "cisplatin eligibility",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Estimated or calculated creatinine clearance ≥ 30ml/min but < 60 ml/min",
            "criterions": [
                {
                    "exact_snippets": "Estimated or calculated creatinine clearance ≥ 30ml/min but < 60 ml/min",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "range",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 30,
                                        "unit": "ml/min"
                                    },
                                    {
                                        "operator": "<",
                                        "value": 60,
                                        "unit": "ml/min"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Grade 2 or above audiometric hearing loss (per CTCAE v4.0)",
            "criterions": [
                {
                    "exact_snippets": "Grade 2 or above audiometric hearing loss (per CTCAE v4.0)",
                    "criterion": "audiometric hearing loss",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Grade 2 or above peripheral neuropathy (per CTCAE v4.0)",
            "criterions": [
                {
                    "exact_snippets": "Grade 2 or above peripheral neuropathy (per CTCAE v4.0)",
                    "criterion": "peripheral neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Availability of tumor specimen block or 30 unstained slides from diagnosis of muscle-invasive disease. Patients with fewer than 30 slides available may be enrolled after discussion with the Principal Investigator.",
            "criterions": [
                {
                    "exact_snippets": "Availability of tumor specimen block or 30 unstained slides from diagnosis of muscle-invasive disease.",
                    "criterion": "tumor specimen",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with fewer than 30 slides available may be enrolled after discussion with the Principal Investigator.",
                    "criterion": "unstained slides",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<",
                                "value": 30,
                                "unit": "slides"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Karnofsky performance status ≥ 70%.",
            "criterions": [
                {
                    "exact_snippets": "Karnofsky performance status ≥ 70%",
                    "criterion": "Karnofsky performance status",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": {
                                "operator": ">=",
                                "value": 70,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Medically appropriate candidate for radical cystectomy, as per MSK Attending Urologic Oncologist",
            "criterions": [
                {
                    "exact_snippets": "Medically appropriate candidate for radical cystectomy",
                    "criterion": "medical appropriateness for radical cystectomy",
                    "requirements": [
                        {
                            "requirement_type": "determination",
                            "expected_value": "as per MSK Attending Urologic Oncologist"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Age ≥ 18 years.",
            "criterions": [
                {
                    "exact_snippets": "Age ≥ 18 years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count ≥ 1.5 x 10^9/L",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count ≥ 1.5 x 10^9/L",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.5,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelets ≥ 100 x 10^9/L",
            "criterions": [
                {
                    "exact_snippets": "Platelets ≥ 100 x 10^9/L",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 100,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Bilirubin ≤1.5 times the upper limit of normal (x ULN)",
            "criterions": [
                {
                    "exact_snippets": "Bilirubin ≤1.5 times the upper limit of normal (x ULN)",
                    "criterion": "bilirubin level",
                    "requirements": [
                        {
                            "requirement_type": "comparison",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "times the upper limit of normal (x ULN)"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN",
            "criterions": [
                {
                    "exact_snippets": "Aspartate transaminase (AST) ... ≤ 3 x ULN",
                    "criterion": "Aspartate transaminase (AST)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alanine transaminase (ALT) ≤ 3 x ULN",
                    "criterion": "alanine transaminase (ALT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "x ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* PTT/PT ≤1.5 x ULN or INR < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.",
            "criterions": [
                {
                    "exact_snippets": "PTT/PT ≤1.5 x ULN",
                    "criterion": "PTT/PT",
                    "requirements": [
                        {
                            "requirement_type": "comparison",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "INR < 1.7 x ULN",
                    "criterion": "INR",
                    "requirements": [
                        {
                            "requirement_type": "comparison",
                            "expected_value": {
                                "operator": "<",
                                "value": 1.7,
                                "unit": "x ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients receiving therapeutic anticoagulation should be on a stable dose",
                    "criterion": "therapeutic anticoagulation",
                    "requirements": [
                        {
                            "requirement_type": "dose stability",
                            "expected_value": "stable"
                        }
                    ]
                }
            ]
        },
        {
            "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": "* Prior treatment with systemic chemotherapy for urothelial cancer, including immune checkpoint inhibitors for non-muscle invasive bladder cancer. (Prior intravesical treatment such as BCG is allowed.)",
            "criterions": [
                {
                    "exact_snippets": "Prior treatment with systemic chemotherapy for urothelial cancer",
                    "criterion": "prior systemic chemotherapy treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "including immune checkpoint inhibitors for non-muscle invasive bladder cancer",
                    "criterion": "prior immune checkpoint inhibitor treatment",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Prior bladder-directed radiotherapy (exclusion applies only to MIBC Cohorts 1 - 3).",
            "criterions": [
                {
                    "exact_snippets": "Prior bladder-directed radiotherapy (exclusion applies only to MIBC Cohorts 1 - 3)",
                    "criterion": "prior bladder-directed radiotherapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Presence of active autoimmune disease, symptoms, or conditions, with the following exceptions:",
            "criterions": [
                {
                    "exact_snippets": "Presence of active autoimmune disease",
                    "criterion": "active autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Presence of ... symptoms",
                    "criterion": "symptoms",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Presence of ... conditions",
                    "criterion": "conditions",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "°Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, asymptomatic laboratory evidence of autoimmune disease (e.g.: +ANA, +RF, anti-thyroglobulin antibodies), or conditions not expected to recur in the absence of an external trigger are permitted to enroll.",
            "criterions": [
                {
                    "exact_snippets": "type I diabetes mellitus",
                    "criterion": "type I diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement",
                    "criterion": "residual hypothyroidism",
                    "requirements": [
                        {
                            "requirement_type": "cause",
                            "expected_value": "autoimmune thyroiditis"
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "hormone replacement"
                        }
                    ]
                },
                {
                    "exact_snippets": "skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment",
                    "criterion": "skin disorders",
                    "requirements": [
                        {
                            "requirement_type": "examples",
                            "expected_value": [
                                "vitiligo",
                                "psoriasis",
                                "alopecia"
                            ]
                        },
                        {
                            "requirement_type": "treatment",
                            "expected_value": "not requiring systemic treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "asymptomatic laboratory evidence of autoimmune disease (e.g.: +ANA, +RF, anti-thyroglobulin antibodies)",
                    "criterion": "asymptomatic laboratory evidence of autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "examples",
                            "expected_value": [
                                "+ANA",
                                "+RF",
                                "anti-thyroglobulin antibodies"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "conditions not expected to recur in the absence of an external trigger",
                    "criterion": "conditions not expected to recur",
                    "requirements": [
                        {
                            "requirement_type": "trigger",
                            "expected_value": "absence of an external trigger"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.",
            "criterions": [
                {
                    "exact_snippets": "condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug",
                    "criterion": "systemic treatment with corticosteroids or immunosuppressive medications",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease",
                    "criterion": "active autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Unstable angina.",
            "criterions": [
                {
                    "exact_snippets": "Unstable angina",
                    "criterion": "unstable angina",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* New York Heart Association (NYHA) Grade II or greater congestive heart failure.",
            "criterions": [
                {
                    "exact_snippets": "New York Heart Association (NYHA) Grade II or greater congestive heart failure",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "NYHA Grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of myocardial infarction within 6 months.",
            "criterions": [
                {
                    "exact_snippets": "History of myocardial infarction within 6 months.",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "timeframe",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of stroke within 6 months.",
            "criterions": [
                {
                    "exact_snippets": "History of stroke within 6 months.",
                    "criterion": "stroke",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 6,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose.",
            "criterions": [
                {
                    "exact_snippets": "Evidence of bleeding diathesis",
                    "criterion": "bleeding diathesis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Evidence of ... coagulopathy",
                    "criterion": "coagulopathy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Therapeutic anticoagulation is permitted",
                    "criterion": "therapeutic anticoagulation",
                    "requirements": [
                        {
                            "requirement_type": "permission",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must be on a stable dose",
                    "criterion": "anticoagulation dose stability",
                    "requirements": [
                        {
                            "requirement_type": "stability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Major surgical procedure within 28 days prior to the study. (Transurethral resection of bladder tumor is permitted",
            "criterions": [
                {
                    "exact_snippets": "Major surgical procedure within 28 days prior to the study",
                    "criterion": "major surgical procedure",
                    "requirements": [
                        {
                            "requirement_type": "time since procedure",
                            "expected_value": {
                                "operator": "<",
                                "value": 28,
                                "unit": "days"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Transurethral resection of bladder tumor is permitted",
                    "criterion": "transurethral resection of bladder tumor",
                    "requirements": [
                        {
                            "requirement_type": "permitted",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Serious, non-healing wound, ulcer, or bone fracture.",
            "criterions": [
                {
                    "exact_snippets": "Serious, non-healing wound",
                    "criterion": "wound",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        },
                        {
                            "requirement_type": "severity",
                            "expected_value": "serious"
                        }
                    ]
                },
                {
                    "exact_snippets": "Serious, non-healing ... ulcer",
                    "criterion": "ulcer",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        },
                        {
                            "requirement_type": "severity",
                            "expected_value": "serious"
                        }
                    ]
                },
                {
                    "exact_snippets": "Serious, non-healing ... bone fracture",
                    "criterion": "bone fracture",
                    "requirements": [
                        {
                            "requirement_type": "healing status",
                            "expected_value": "non-healing"
                        },
                        {
                            "requirement_type": "severity",
                            "expected_value": "serious"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Other prior malignancy active within the previous 2 years except for local or organ-confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study.",
            "criterions": [
                {
                    "exact_snippets": "Other prior malignancy active within the previous 2 years",
                    "criterion": "prior malignancy",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "timeframe",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "local or organ-confined early stage cancer that has been definitively treated with curative intent",
                    "criterion": "early stage cancer",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": "curative intent"
                        }
                    ]
                },
                {
                    "exact_snippets": "does not require treatment",
                    "criterion": "early stage cancer",
                    "requirements": [
                        {
                            "requirement_type": "treatment requirement",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "does not require ongoing treatment",
                    "criterion": "early stage cancer",
                    "requirements": [
                        {
                            "requirement_type": "ongoing treatment requirement",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "has no evidence of active disease",
                    "criterion": "early stage cancer",
                    "requirements": [
                        {
                            "requirement_type": "disease activity",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "has a negligible risk of recurrence",
                    "criterion": "early stage cancer",
                    "requirements": [
                        {
                            "requirement_type": "recurrence risk",
                            "expected_value": "negligible"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other medicines specifically targeting T cells are prohibited. Prior IL-2 is permitted.",
            "criterions": [
                {
                    "exact_snippets": "Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other medicines specifically targeting T cells are prohibited.",
                    "criterion": "prior therapy with T cell co-stimulation or checkpoint pathways",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Prior IL-2 is permitted.",
                    "criterion": "prior IL-2 therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Prior therapy with intravesical BCG within 6 weeks of treatment.",
            "criterions": [
                {
                    "exact_snippets": "Prior therapy with intravesical BCG",
                    "criterion": "prior therapy",
                    "requirements": [
                        {
                            "requirement_type": "treatment type",
                            "expected_value": "intravesical BCG"
                        }
                    ]
                },
                {
                    "exact_snippets": "within 6 weeks of treatment",
                    "criterion": "time since prior therapy",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection.",
            "criterions": [
                {
                    "exact_snippets": "Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test",
                    "criterion": "hepatitis B virus (HBV)",
                    "requirements": [
                        {
                            "requirement_type": "test result",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection",
                    "criterion": "hepatitis C virus (HCV)",
                    "requirements": [
                        {
                            "requirement_type": "test result",
                            "expected_value": "positive"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).",
            "criterions": [
                {
                    "exact_snippets": "Known history of testing positive for human immunodeficiency virus (HIV)",
                    "criterion": "HIV status",
                    "requirements": [
                        {
                            "requirement_type": "history of positive test",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "known acquired immunodeficiency syndrome (AIDS)",
                    "criterion": "AIDS status",
                    "requirements": [
                        {
                            "requirement_type": "known presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of allergy to study drug component or history of severe hypersensitivity reaction to any monoclonal antibody.",
            "criterions": [
                {
                    "exact_snippets": "History of allergy to study drug component",
                    "criterion": "allergy to study drug component",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "history of severe hypersensitivity reaction to any monoclonal antibody",
                    "criterion": "severe hypersensitivity reaction to monoclonal antibody",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Women who are breastfeeding or pregnant as evidenced by a positive pregnancy test within 14 days of first dose.",
            "criterions": [
                {
                    "exact_snippets": "Women who are breastfeeding",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Women who are ... pregnant",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "positive pregnancy test within 14 days of first dose",
                    "criterion": "pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "positive"
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 14 days of first dose"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover).",
            "criterions": [
                {
                    "exact_snippets": "Male subjects",
                    "criterion": "gender",
                    "requirements": [
                        {
                            "requirement_type": "expected_value",
                            "expected_value": "male"
                        }
                    ]
                },
                {
                    "exact_snippets": "unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment",
                    "criterion": "contraception use",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle).",
            "criterions": [
                {
                    "exact_snippets": "Women of childbearing potential (WOCBP)",
                    "criterion": "women of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "not using a medically acceptable means of contraception",
                    "criterion": "use of contraception",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "throughout the study treatment and for at least 23 weeks following the last dose of study treatment",
                    "criterion": "duration of contraception use",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": "throughout the study treatment and for at least 23 weeks following the last dose of study treatment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* WOCBP are defined as those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post-menopausal is defined as:",
            "criterions": [
                {
                    "exact_snippets": "experienced menarche",
                    "criterion": "menarche",
                    "requirements": [
                        {
                            "requirement_type": "experience",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)",
                    "criterion": "surgical sterilization",
                    "requirements": [
                        {
                            "requirement_type": "procedure",
                            "expected_value": [
                                "hysterectomy",
                                "bilateral tubal ligation",
                                "bilateral oophorectomy"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "postmenopausal",
                    "criterion": "menopausal status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "postmenopausal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Amenorrhea ≥ 12 consecutive months without another cause, or",
            "criterions": [
                {
                    "exact_snippets": "Amenorrhea ≥ 12 consecutive months",
                    "criterion": "amenorrhea",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 12,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL",
            "criterions": [
                {
                    "exact_snippets": "women with irregular menstrual periods",
                    "criterion": "irregular menstrual periods",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "on hormone replacement therapy (HRT)",
                    "criterion": "hormone replacement therapy (HRT)",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL",
                    "criterion": "serum follicle stimulating hormone (FSH) level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">",
                                "value": 35,
                                "unit": "mIU/mL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.",
            "criterions": [
                {
                    "exact_snippets": "compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness",
                    "criterion": "compulsory detention for treatment",
                    "requirements": [
                        {
                            "requirement_type": "condition",
                            "expected_value": [
                                "psychiatric illness",
                                "physical illness (e.g., infectious disease)"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Inability to comply with study and/or follow-up procedures.",
            "criterions": [
                {
                    "exact_snippets": "Inability to comply with study and/or follow-up procedures.",
                    "criterion": "compliance with study and follow-up procedures",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [
        {
            "line": "* Required initial laboratory values:",
            "criterions": []
        }
    ],
    "failed_exclusion": [],
    "failed_miscellaneous": []
}