{
    "info": {
        "nct_id": "NCT03425331",
        "official_title": "Biomarkers of Response to Ipilimumab and Nivolumab as First-line Therapy for Metastatic Non-small Cell Lung Cancer (NSCLC): an Open-label, Single Arm Phase 2 Study",
        "inclusion_criteria": "* Histologically confirmed stage IV NSCLC, with no prior systemic anti-cancer therapy of any kind (including EGFR and ALK inhibitors). Prior definitive chemoradiation for locally advanced disease is permitted as long as the last administration of chemotherapy or radiation (whichever was given last) occurred at least 6 months prior to enrollment. Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment.\n* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.\n* Age ≥ 18 years.\n* ECOG performance status ≤ 1 (see Appendix A)\n* Participants must have normal organ and marrow function as defined below:\n\n  * Absolute neutrophil count ≥ 1,500/mcL\n  * Platelets ≥ 100,000/mcL\n  * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)\n  * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, OR\n  * AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN if liver metastases are present\n  * Serum creatinine ≤ 1.5 × institutional ULN, OR\n  * Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels above 1.5 × institutional ULN.\n* Ability to understand and the willingness to sign a written informed consent document.\n* Participants must have a tumor tissue sample available (formalin-fixed paraffin embedded [FFPE] tissue block or unstained slides); may be newly obtained or obtained within 6 months prior to enrollment (without systemic therapy given after the sample was obtained). Participants without sufficient archival tissue may be enrolled following successful completion of the pre-treatment tumor tissue biopsy. Tissue must be a core needle biopsy, excisional, or incisional biopsy. Fine needle aspirates (FNA) or malignant effusions are not adequate. Bone biopsies without a soft tissue component are not adequate.\n* The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol who are not azoospermic who are sexually active with WOCBP must agree to follow instructions for acceptable contraception from the time of signing consent, and for 31 weeks after their last dose of protocol-indicated treatment.\n* Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy. Participants must also be willing to undergo an on-treatment tumor tissue biopsy if clinically feasible.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "* Participants with known EGFR mutations or ALK rearrangements. All subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation.\n* Participants who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.\n* Participants who received prior non-CNS directed palliative radiation therapy within 7 days of the date of study entry.\n* Participants who are receiving any other investigational agents.\n* Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to study entry. Subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first study treatment.\n* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or nivolumab.\n* Participants with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to first treatment and no additional therapy is required or anticipated to be required during the study period as judged by the treating investigator. Exceptions include non-melanoma skin cancers, and in situ cancers of any type (e.g. bladder, gastric, colon, cervical/dysplasia, melanoma, or breast carcinoma in situ).\n* Participants with any other active malignancy requiring concurrent intervention.\n* Participants with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.\n* Participants with a condition requiring systemic treatment with corticosteroids of > 10 mg daily prednisone (or equivalent), or subjects requiring other immunosuppressive medications within 14 days of first treatment. Inhaled, topical, ophthalmologic, local steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.\n* Participants with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity in the opinion of the treating investigator.\n* Participants with a known history of testing positive for human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS).\n* Participants with known positive test for hepatitis B or C indicating acute or chronic infection.\n* Participants with ≥ Grade 2 peripheral neuropathy.\n* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.\n* Pregnant women are excluded from this study because ipilimumab and nivolumab are both agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ipilimumab or nivolumab, breastfeeding should be discontinued if the mother is treated with ipilimumab or nivolumab. A negative serum pregnancy test is required prior to study entry.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* Histologically confirmed stage IV NSCLC, with no prior systemic anti-cancer therapy of any kind (including EGFR and ALK inhibitors). Prior definitive chemoradiation for locally advanced disease is permitted as long as the last administration of chemotherapy or radiation (whichever was given last) occurred at least 6 months prior to enrollment. Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment.",
            "criterions": [
                {
                    "exact_snippets": "Histologically confirmed stage IV NSCLC",
                    "criterion": "NSCLC stage",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": "histologically confirmed"
                        },
                        {
                            "requirement_type": "stage",
                            "expected_value": "IV"
                        }
                    ]
                },
                {
                    "exact_snippets": "no prior systemic anti-cancer therapy of any kind (including EGFR and ALK inhibitors)",
                    "criterion": "prior systemic anti-cancer therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Prior definitive chemoradiation for locally advanced disease is permitted ... last administration of chemotherapy or radiation (whichever was given last) occurred at least 6 months prior to enrollment",
                    "criterion": "prior definitive chemoradiation for locally advanced disease",
                    "requirements": [
                        {
                            "requirement_type": "time since last administration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment",
                    "criterion": "prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer",
                    "requirements": [
                        {
                            "requirement_type": "time since completion",
                            "expected_value": {
                                "operator": ">=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.",
            "criterions": [
                {
                    "exact_snippets": "Participants must have measurable disease",
                    "criterion": "measurable disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "at least one lesion that can be accurately measured in at least one dimension",
                    "criterion": "lesion measurement",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "lesion"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions",
                    "criterion": "lesion measurement method",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": [
                                "longest diameter for non-nodal lesions",
                                "short axis for nodal lesions"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "as ≥20 mm with conventional techniques",
                    "criterion": "lesion size with conventional techniques",
                    "requirements": [
                        {
                            "requirement_type": "size",
                            "expected_value": {
                                "operator": ">=",
                                "value": 20,
                                "unit": "mm"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam",
                    "criterion": "lesion size with advanced techniques",
                    "requirements": [
                        {
                            "requirement_type": "size",
                            "expected_value": {
                                "operator": ">=",
                                "value": 10,
                                "unit": "mm"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Age ≥ 18 years.",
            "criterions": [
                {
                    "exact_snippets": "Age ≥ 18 years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* ECOG performance status ≤ 1 (see Appendix A)",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status ≤ 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants must have normal organ and marrow function as defined below:",
            "criterions": [
                {
                    "exact_snippets": "normal organ and marrow function",
                    "criterion": "organ and marrow function",
                    "requirements": [
                        {
                            "requirement_type": "functionality",
                            "expected_value": "normal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count ≥ 1,500/mcL",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count ≥ 1,500/mcL",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelets ≥ 100,000/mcL",
            "criterions": [
                {
                    "exact_snippets": "Platelets ≥ 100,000/mcL",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 100000,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "× institutional upper limit of normal (ULN)"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, OR",
            "criterions": [
                {
                    "exact_snippets": "AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN",
                    "criterion": "AST(SGOT)/ALT(SGPT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "× institutional ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN if liver metastases are present",
            "criterions": [
                {
                    "exact_snippets": "AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN",
                    "criterion": "AST(SGOT)/ALT(SGPT) levels",
                    "requirements": [
                        {
                            "requirement_type": "comparison",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "institutional ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "if liver metastases are present",
                    "criterion": "liver metastases",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Serum creatinine ≤ 1.5 × institutional ULN, OR",
            "criterions": [
                {
                    "exact_snippets": "Serum creatinine ≤ 1.5 × institutional ULN",
                    "criterion": "serum creatinine",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "institutional ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels above 1.5 × institutional ULN.",
            "criterions": [
                {
                    "exact_snippets": "Creatinine clearance ≥ 60 mL/min/1.73 m2",
                    "criterion": "creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 60,
                                "unit": "mL/min/1.73 m2"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "serum creatinine levels above 1.5 × institutional ULN",
                    "criterion": "serum creatinine levels",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 1.5,
                                "unit": "× institutional ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Ability to understand and the willingness to sign a written informed consent document.",
            "criterions": [
                {
                    "exact_snippets": "Ability to understand",
                    "criterion": "cognitive ability",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "willingness to sign a written informed consent document",
                    "criterion": "willingness to consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants must have a tumor tissue sample available (formalin-fixed paraffin embedded [FFPE] tissue block or unstained slides); may be newly obtained or obtained within 6 months prior to enrollment (without systemic therapy given after the sample was obtained). Participants without sufficient archival tissue may be enrolled following successful completion of the pre-treatment tumor tissue biopsy. Tissue must be a core needle biopsy, excisional, or incisional biopsy. Fine needle aspirates (FNA) or malignant effusions are not adequate. Bone biopsies without a soft tissue component are not adequate.",
            "criterions": [
                {
                    "exact_snippets": "tumor tissue sample available",
                    "criterion": "tumor tissue sample",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "formalin-fixed paraffin embedded [FFPE] tissue block or unstained slides",
                    "criterion": "tumor tissue sample type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "formalin-fixed paraffin embedded [FFPE] tissue block",
                                "unstained slides"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "may be newly obtained or obtained within 6 months prior to enrollment",
                    "criterion": "tumor tissue sample acquisition time",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": "newly obtained or within 6 months prior to enrollment"
                        }
                    ]
                },
                {
                    "exact_snippets": "without systemic therapy given after the sample was obtained",
                    "criterion": "systemic therapy post-sample",
                    "requirements": [
                        {
                            "requirement_type": "absence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "sufficient archival tissue",
                    "criterion": "sufficient archival tissue",
                    "requirements": [
                        {
                            "requirement_type": "sufficiency",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "successful completion of the pre-treatment tumor tissue biopsy",
                    "criterion": "pre-treatment tumor tissue biopsy",
                    "requirements": [
                        {
                            "requirement_type": "completion",
                            "expected_value": "successful"
                        }
                    ]
                },
                {
                    "exact_snippets": "Tissue must be a core needle biopsy, excisional, or incisional biopsy",
                    "criterion": "biopsy type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "core needle biopsy",
                                "excisional biopsy",
                                "incisional biopsy"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Fine needle aspirates (FNA) or malignant effusions are not adequate",
                    "criterion": "fine needle aspirates or malignant effusions",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Bone biopsies without a soft tissue component are not adequate",
                    "criterion": "bone biopsies without soft tissue component",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol who are not azoospermic who are sexually active with WOCBP must agree to follow instructions for acceptable contraception from the time of signing consent, and for 31 weeks after their last dose of protocol-indicated treatment.",
            "criterions": [
                {
                    "exact_snippets": "women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception",
                    "criterion": "contraception agreement for women of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "23 weeks after their last dose of protocol-indicated treatment",
                    "criterion": "contraception duration for women of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 23,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Men treated or enrolled on this protocol who are not azoospermic who are sexually active with WOCBP must agree to follow instructions for acceptable contraception",
                    "criterion": "contraception agreement for men not azoospermic",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "31 weeks after their last dose of protocol-indicated treatment",
                    "criterion": "contraception duration for men not azoospermic",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 31,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy. Participants must also be willing to undergo an on-treatment tumor tissue biopsy if clinically feasible.",
            "criterions": [
                {
                    "exact_snippets": "Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy.",
                    "criterion": "pre-treatment tumor tissue biopsy",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Participants must also be willing to undergo an on-treatment tumor tissue biopsy if clinically feasible.",
                    "criterion": "on-treatment tumor tissue biopsy",
                    "requirements": [
                        {
                            "requirement_type": "willingness",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "clinical feasibility",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must 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": "* Participants with known EGFR mutations or ALK rearrangements. All subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation.",
            "criterions": [
                {
                    "exact_snippets": "known EGFR mutations",
                    "criterion": "EGFR mutation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "ALK rearrangements",
                    "criterion": "ALK rearrangement",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "known to have a KRAS mutation",
                    "criterion": "KRAS mutation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants who received prior non-CNS directed palliative radiation therapy within 7 days of the date of study entry.",
            "criterions": [
                {
                    "exact_snippets": "Participants who received prior non-CNS directed palliative radiation therapy within 7 days of the date of study entry.",
                    "criterion": "prior non-CNS directed palliative radiation therapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 7,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants who are receiving any other investigational agents.",
            "criterions": [
                {
                    "exact_snippets": "Participants who are receiving any other investigational agents",
                    "criterion": "receiving investigational agents",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to study entry. Subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first study treatment.",
            "criterions": [
                {
                    "exact_snippets": "known untreated brain metastases",
                    "criterion": "untreated brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "CNS metastases are adequately treated",
                    "criterion": "CNS metastases treatment",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "neurologically returned to baseline ... for at least 2 weeks prior to study entry",
                    "criterion": "neurologic status",
                    "requirements": [
                        {
                            "requirement_type": "baseline return duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first study treatment",
                    "criterion": "corticosteroid use",
                    "requirements": [
                        {
                            "requirement_type": "dose stability",
                            "expected_value": [
                                "off",
                                "stable",
                                "decreasing"
                            ]
                        },
                        {
                            "requirement_type": "dose amount",
                            "expected_value": {
                                "operator": "<=",
                                "value": 10,
                                "unit": "mg"
                            }
                        },
                        {
                            "requirement_type": "dose duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or nivolumab.",
            "criterions": [
                {
                    "exact_snippets": "History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or nivolumab.",
                    "criterion": "allergic reactions",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "attribution",
                            "expected_value": "compounds of similar chemical or biologic composition to ipilimumab or nivolumab"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to first treatment and no additional therapy is required or anticipated to be required during the study period as judged by the treating investigator. Exceptions include non-melanoma skin cancers, and in situ cancers of any type (e.g. bladder, gastric, colon, cervical/dysplasia, melanoma, or breast carcinoma in situ).",
            "criterions": [
                {
                    "exact_snippets": "Participants with previous malignancies are excluded",
                    "criterion": "previous malignancies",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "unless a complete remission was achieved at least 2 years prior to first treatment",
                    "criterion": "complete remission",
                    "requirements": [
                        {
                            "requirement_type": "time since remission",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "no additional therapy is required or anticipated to be required during the study period",
                    "criterion": "additional therapy",
                    "requirements": [
                        {
                            "requirement_type": "requirement",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Exceptions include non-melanoma skin cancers, and in situ cancers of any type",
                    "criterion": "exceptions for previous malignancies",
                    "requirements": [
                        {
                            "requirement_type": "types",
                            "expected_value": [
                                "non-melanoma skin cancers",
                                "in situ cancers"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with any other active malignancy requiring concurrent intervention.",
            "criterions": [
                {
                    "exact_snippets": "any other active malignancy requiring concurrent intervention",
                    "criterion": "active malignancy",
                    "requirements": [
                        {
                            "requirement_type": "intervention requirement",
                            "expected_value": "concurrent"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.",
            "criterions": [
                {
                    "exact_snippets": "active, known, or suspected autoimmune disease",
                    "criterion": "autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "type I diabetes mellitus",
                    "criterion": "type I diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "hypothyroidism only requiring hormone replacement",
                    "criterion": "hypothyroidism",
                    "requirements": [
                        {
                            "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": "treatment",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "conditions not expected to recur in the absence of an external trigger",
                    "criterion": "conditions not expected to recur",
                    "requirements": [
                        {
                            "requirement_type": "recurrence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with a condition requiring systemic treatment with corticosteroids of > 10 mg daily prednisone (or equivalent), or subjects requiring other immunosuppressive medications within 14 days of first treatment. Inhaled, topical, ophthalmologic, local steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.",
            "criterions": [
                {
                    "exact_snippets": "condition requiring systemic treatment with corticosteroids of > 10 mg daily prednisone (or equivalent)",
                    "criterion": "systemic corticosteroid treatment",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 10,
                                "unit": "mg daily prednisone (or equivalent)"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "subjects requiring other immunosuppressive medications within 14 days of first treatment",
                    "criterion": "immunosuppressive medication requirement",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within 14 days of first treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "Inhaled, topical, ophthalmologic, local steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or equivalent are permitted",
                    "criterion": "steroid use",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "Inhaled",
                                "topical",
                                "ophthalmologic",
                                "local steroid injections",
                                "adrenal replacement"
                            ]
                        },
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 10,
                                "unit": "mg daily prednisone or equivalent"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "in the absence of active autoimmune disease",
                    "criterion": "active autoimmune disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity in the opinion of the treating investigator.",
            "criterions": [
                {
                    "exact_snippets": "interstitial lung disease that is symptomatic",
                    "criterion": "interstitial lung disease",
                    "requirements": [
                        {
                            "requirement_type": "symptomatic",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "interstitial lung disease ... may interfere with the detection or management of suspected drug-related pulmonary toxicity",
                    "criterion": "interstitial lung disease",
                    "requirements": [
                        {
                            "requirement_type": "interference with detection or management of pulmonary toxicity",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with a 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 testing positive",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "known acquired immunodeficiency syndrome (AIDS)",
                    "criterion": "AIDS status",
                    "requirements": [
                        {
                            "requirement_type": "known",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with ≥ Grade 2 peripheral neuropathy.",
            "criterions": [
                {
                    "exact_snippets": "≥ Grade 2 peripheral neuropathy",
                    "criterion": "peripheral neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "Grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.",
            "criterions": [
                {
                    "exact_snippets": "Uncontrolled intercurrent illness ... ongoing or active infection",
                    "criterion": "ongoing or active infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled intercurrent illness ... symptomatic congestive heart failure",
                    "criterion": "symptomatic congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled intercurrent illness ... unstable angina pectoris",
                    "criterion": "unstable angina pectoris",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled intercurrent illness ... cardiac arrhythmia",
                    "criterion": "cardiac arrhythmia",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Uncontrolled intercurrent illness ... psychiatric illness/social situations that would limit compliance with study requirements",
                    "criterion": "psychiatric illness/social situations",
                    "requirements": [
                        {
                            "requirement_type": "impact on compliance",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Pregnant women are excluded from this study because ipilimumab and nivolumab are both agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ipilimumab or nivolumab, breastfeeding should be discontinued if the mother is treated with ipilimumab or nivolumab. A negative serum pregnancy test is required prior to study entry.",
            "criterions": [
                {
                    "exact_snippets": "Pregnant women are excluded",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "A negative serum pregnancy test is required",
                    "criterion": "serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                },
                {
                    "exact_snippets": "breastfeeding should be discontinued",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [
        {
            "line": "* Participants who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.",
            "criterions": [
                {
                    "exact_snippets": "prior treatment with an anti-PD-1",
                    "criterion": "prior treatment with anti-PD-1 antibody",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior treatment with an anti-PD-L1",
                    "criterion": "prior treatment with anti-PD-L1 antibody",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior treatment with an anti-PD-L2",
                    "criterion": "prior treatment with anti-PD-L2 antibody",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior treatment with an anti-CTLA-4 antibody",
                    "criterion": "prior treatment with anti-CTLA-4 antibody",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "prior treatment with ... any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways",
                    "criterion": "prior treatment with antibody or drug targeting T-cell co-stimulation or checkpoint pathways",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Participants with known positive test for hepatitis B or C indicating acute or chronic infection.",
            "criterions": [
                {
                    "exact_snippets": "known positive test for hepatitis B",
                    "criterion": "hepatitis B infection",
                    "requirements": [
                        {
                            "requirement_type": "test result",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "known positive test for hepatitis C",
                    "criterion": "hepatitis C infection",
                    "requirements": [
                        {
                            "requirement_type": "test result",
                            "expected_value": "positive"
                        }
                    ]
                }
            ]
        }
    ],
    "failed_miscellaneous": []
}