{
    "info": {
        "nct_id": "NCT04541082",
        "official_title": "A First-in-human Phase I Single-agent Dose-escalation, Food Effect and Dose Expansion Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms",
        "inclusion_criteria": "Patients must meet all the following criteria to participate in the study:\n\n1. Patients aged ≥18 years with a recurrent, primary CNS neoplasm. For all cohorts, patients must have a histologically confirmed primary CNS neoplasm. Primary CNS neoplasms in this study include, but are not limited to, the following: glioblastoma and glioblastoma histologic subtypes, gliosarcoma, primary CNS sarcomas, anaplastic glial neoplasms including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed neuronal-glial tumors, and pilocytic astrocytoma with anaplastic features, diffuse astrocytoma, oligodendroglioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, diffuse midline gliomas and histone mutated gliomas (NOTE: Patients with H3 K27M-mutant diffuse gliomas are excluded unless the primary tumor is located in the pons or spinal cord, or the patient has completed front line radiation or received ONC201 therapy prior to 01 January 2023), ependymoma, anaplastic ependymoma, and all ependymoma subtypes, medulloblastoma and all medulloblastoma subtypes, atypical teratoid/rhabdoid tumor, primary CNS embryonal/primitive neuroectodermal tumors, atypical and anaplastic meningiomas, choroid plexus tumors, and pineal region tumors.\n2. Patients must have recurrent and measurable disease as defined by RANO criteria, using either the HGG and/or LGG RANO criteria based on tumor type, after having received established standard of care treatment for their disease and have no standard treatment options available as determined by the investigators. There is no limit on the number of total recurrences or prior therapies. However, prior therapies with known clinical benefit (including radiation) for specific tumor types are required. If patients are deemed ineligible for such therapies in the opinion of the Investigator, the Investigator must document the reason the patient is considered ineligible.\n3. Patients must have a Karnofsky Performance Score (KPS) of greater than or equal to 70. Patients with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be considered eligible.\n4. (Inclusion Criterion #4 was removed in Amendment 3.)\n5. Patients must not have received prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose of study drug (Cycle 1, Day 1); 42 days in the case of nitrosoureas; 42 days in the case of bevacizumab; 28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent; 14 days in the case of radiotherapy.\n6. (Inclusion Criterion #6 was removed in Amendment 7.)\n7. Patients with AEs Grade ≥2 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have all their AEs resolved prior to the first dose of study drug (Cycle 1, Day 1), except for alopecia or neuropathy; Grade 1 or 2 lymphopenia is allowed.\n8. Patients must not have undergone major surgery 4 weeks prior to the first dose of study drug (Cycle 1, Day 1) and must have completely recovered from any surgery (minor surgical procedures such as skin biopsies and port placement done on an outpatient basis do not require a waiting period).\n9. Patients must have normal organ and marrow function as defined below:\n\n   * Absolute neutrophil count (ANC) ≥1,500/mcL.\n   * Platelets ≥100,000/mcL.\n   * Hemoglobin ≥9.0 mg/dL without transfusion in 2 prior weeks.\n   * Total bilirubin ≤1.5 × upper limit of normal (ULN) (patients with Gilbert's syndrome may be included with total bilirubin >1.5 × ULN if direct bilirubin is ≤1.5 × ULN).\n   * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × ULN.\n   * Measured or estimated creatinine clearance (CLcr) ≥40 mL/minute for patients with creatinine levels above normal. CLcr will be calculated by the Cockcroft-Gault equation for renal function.\n10. (Inclusion Criterion #10 was removed in Amendment 3)\n11. Patients must provide a tumor specimen (paraffin-embedded block and/or frozen tissue) from a prior resection or biopsy available that is sufficient to perform biomarker assays, ≥15 unstained slides for immunohistochemistry (IHC) analysis must be received by the NOB by the first dose of study drug (Cycle 1, Day 1). For patients with ≥10 to <15 slides, eligibility will be reviewed on a case-by-case basis.\n12. Dependent upon dose level assignment and drug formulation (i.e., capsules versus powder in bottle [PIB]), patients must be able to either swallow oral capsules or swallow liquids.\n13. Patients must provide study-specific informed consent prior to enrollment. No Durable Power of Attorney or Next of Kin can provide initial consent.\n14. Patients must be able to tolerate a magnetic resonance imaging (MRI) study with intravenous gadolinium contrast.\n15. (Inclusion Criterion #15 was removed in Amendment 6)\n16. Patients must have a negative COVID-19 test within 72 hours of the first dose of study drug (Cycle 1, Day 1). Patients who had documented COVID-19 infection within 90 days of treatment but more than 20 days from infection do not need to be tested.\n17. (Inclusion Criterion #17 was removed in Amendment 6)\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "Patients who meet any of the following criteria will be excluded from the study:\n\n1. (Exclusion Criterion #1 was removed in Amendment 3)\n2. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206 (e.g., ONC201) or its excipients.\n3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.\n4. Patients who are unable or unwilling to abide by the study protocol or cooperate fully with the Investigator.\n5. Patients with a known HIV-positive test on combination anti-retroviral therapy are ineligible for this initial first-in-human trial because of the potential for PK interactions with ONC206.\n6. Patients with active cardiac disease, including any of the following:\n\n   * Corrected QT interval (QTc) ≥470 msec on screening electrocardiogram (ECG; using the QTc by Fridericia's [QTcF] formula);\n   * Angina pectoris that requires the use of anti-anginal medication;\n   * Ventricular arrhythmias except for benign premature ventricular contractions;\n   * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;\n   * Conduction abnormality requiring a pacemaker;\n   * Valvular disease with documented compromise in cardiac function; and/or\n   * Symptomatic pericarditis.\n7. Patients with a history of cardiac dysfunction including any of the following:\n\n   * Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction function;\n   * History of documented congestive heart failure (New York Heart Association functional classification III-IV); and/or\n   * Documented cardiomyopathy.\n8. Patients who have had an ischemic or hemorrhagic stroke in the last 3 months. If the patient has had a recent tumor resection, cerebral ischemic or hemorrhagic changes that occur peri operatively are not an exclusion.\n9. Patients with refractory epilepsy are excluded. Patients with primarily or secondarily generalized seizures in the 28 days prior to study enrollment will be excluded. Peri-operative seizures, defined as seizures occurring within the 7 days after a stereotactic biopsy, open biopsy, or surgical resection will not be an exclusion as long as the patient has had no generalized seizures starting 8 days after the surgical procedure. Patients with prior seizures must be on stable doses of 1 or 2 seizure medications for at least 14 days prior to study enrollment.\n10. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC206 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).\n11. Patients who have been treated with any hematopoietic colony-stimulating growth factors (CSFs) (e.g., granulocyte-CSF, granulocyte-macrophage-CSF) ≤2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued.\n12. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin derivative anticoagulant.\n13. Patients who are taking strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, 2D6, 1A2, 2C9, and 2C19 within at least 14 days prior to the first dose of study drug (Cycle 1, Day 1); these medications are excluded throughout the study.\n14. Women who are pregnant or breast feeding.\n15. Women of child-bearing potential with a positive serum pregnancy test ≤72 hours prior to the first dose of study drug (Cycle 1, Day 1).\n16. Patients who are receiving concomitant standard and/or investigational anti-cancer therapy.\n17. Patients with alcohol or substance abuse which, in the opinion of the Investigator, would interfere with compliance or safety.\n18. Patients with the presence of any other serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with patients' safety, obtaining informed consent or compliance to the study procedures as determined by the Investigators.\n19. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, or men who do not agree to use highly effective contraception during treatment and for 16 additional weeks after the final dose of study drug.\n\n    Highly effective contraception is defined as either:\n    * True abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.\n    * Sterilization: Females must have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.\n    * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.\n    * If patients are not practicing true abstinence and/or if the patient or sexual partner have not had a sterilization procedure as listed above, patients and their sexual partners must follow double barrier contraception in accordance with the guidelines for contraception below:\n\n      * Females of childbearing potential:\n\n        * Must use an intrauterine device or intrauterine system, during dosing of any study agent and for 16 weeks after final dose of study drug; or\n        * Must use a double barrier method of contraception: use of an occlusive cap (diaphragm or cervical/vault cap) with spermicide for women combined with use of a condom by their male partners capable of conceiving offspring.\n      * Males capable of conceiving offspring must use condoms during dosing of study agent and for an additional 16 weeks after final dose of study drug.\n\n    Note: Oral, implantable, or injectable contraceptives may be affected by CYP interactions, and are therefore not considered effective for this study.\n20. Previous receipt of ONC201, placebo, or blinded study drug from an ONC201 clinical study, or from any other source for H3 K27M-mutant diffuse glioma on or after 01 January 2023.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "1. Patients aged ≥18 years with a recurrent, primary CNS neoplasm. For all cohorts, patients must have a histologically confirmed primary CNS neoplasm. Primary CNS neoplasms in this study include, but are not limited to, the following: glioblastoma and glioblastoma histologic subtypes, gliosarcoma, primary CNS sarcomas, anaplastic glial neoplasms including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed neuronal-glial tumors, and pilocytic astrocytoma with anaplastic features, diffuse astrocytoma, oligodendroglioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, diffuse midline gliomas and histone mutated gliomas (NOTE: Patients with H3 K27M-mutant diffuse gliomas are excluded unless the primary tumor is located in the pons or spinal cord, or the patient has completed front line radiation or received ONC201 therapy prior to 01 January 2023), ependymoma, anaplastic ependymoma, and all ependymoma subtypes, medulloblastoma and all medulloblastoma subtypes, atypical teratoid/rhabdoid tumor, primary CNS embryonal/primitive neuroectodermal tumors, atypical and anaplastic meningiomas, choroid plexus tumors, and pineal region tumors.",
            "criterions": [
                {
                    "exact_snippets": "Patients aged ≥18 years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "recurrent, primary CNS neoplasm",
                    "criterion": "CNS neoplasm recurrence",
                    "requirements": [
                        {
                            "requirement_type": "recurrence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "histologically confirmed primary CNS neoplasm",
                    "criterion": "CNS neoplasm histological confirmation",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Primary CNS neoplasms in this study include, but are not limited to, the following: glioblastoma and glioblastoma histologic subtypes, gliosarcoma, primary CNS sarcomas, anaplastic glial neoplasms including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed neuronal-glial tumors, and pilocytic astrocytoma with anaplastic features, diffuse astrocytoma, oligodendroglioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, diffuse midline gliomas and histone mutated gliomas",
                    "criterion": "CNS neoplasm type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "glioblastoma",
                                "glioblastoma histologic subtypes",
                                "gliosarcoma",
                                "primary CNS sarcomas",
                                "anaplastic glial neoplasms",
                                "anaplastic astrocytoma",
                                "anaplastic oligodendroglioma",
                                "anaplastic mixed neuronal-glial tumors",
                                "pilocytic astrocytoma with anaplastic features",
                                "diffuse astrocytoma",
                                "oligodendroglioma",
                                "gliomatosis cerebri",
                                "pleomorphic xanthoastrocytoma",
                                "anaplastic pleomorphic xanthoastrocytoma",
                                "diffuse midline gliomas",
                                "histone mutated gliomas"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with H3 K27M-mutant diffuse gliomas are excluded unless the primary tumor is located in the pons or spinal cord, or the patient has completed front line radiation or received ONC201 therapy prior to 01 January 2023",
                    "criterion": "H3 K27M-mutant diffuse gliomas",
                    "requirements": [
                        {
                            "requirement_type": "exclusion",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "pons",
                                "spinal cord"
                            ]
                        },
                        {
                            "requirement_type": "treatment completion",
                            "expected_value": [
                                "front line radiation",
                                "ONC201 therapy prior to 01 January 2023"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "ependymoma, anaplastic ependymoma, and all ependymoma subtypes, medulloblastoma and all medulloblastoma subtypes, atypical teratoid/rhabdoid tumor, primary CNS embryonal/primitive neuroectodermal tumors, atypical and anaplastic meningiomas, choroid plexus tumors, and pineal region tumors",
                    "criterion": "CNS neoplasm type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "ependymoma",
                                "anaplastic ependymoma",
                                "all ependymoma subtypes",
                                "medulloblastoma",
                                "all medulloblastoma subtypes",
                                "atypical teratoid/rhabdoid tumor",
                                "primary CNS embryonal/primitive neuroectodermal tumors",
                                "atypical and anaplastic meningiomas",
                                "choroid plexus tumors",
                                "pineal region tumors"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Patients must have recurrent and measurable disease as defined by RANO criteria, using either the HGG and/or LGG RANO criteria based on tumor type, after having received established standard of care treatment for their disease and have no standard treatment options available as determined by the investigators. There is no limit on the number of total recurrences or prior therapies. However, prior therapies with known clinical benefit (including radiation) for specific tumor types are required. If patients are deemed ineligible for such therapies in the opinion of the Investigator, the Investigator must document the reason the patient is considered ineligible.",
            "criterions": [
                {
                    "exact_snippets": "recurrent and measurable disease",
                    "criterion": "disease status",
                    "requirements": [
                        {
                            "requirement_type": "recurrence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "measurability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "as defined by RANO criteria",
                    "criterion": "RANO criteria",
                    "requirements": [
                        {
                            "requirement_type": "compliance",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "using either the HGG and/or LGG RANO criteria based on tumor type",
                    "criterion": "RANO criteria type",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "HGG",
                                "LGG"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "after having received established standard of care treatment",
                    "criterion": "standard of care treatment",
                    "requirements": [
                        {
                            "requirement_type": "completion",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "have no standard treatment options available",
                    "criterion": "standard treatment options",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "prior therapies with known clinical benefit (including radiation) for specific tumor types are required",
                    "criterion": "prior therapies with known clinical benefit",
                    "requirements": [
                        {
                            "requirement_type": "completion",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "If patients are deemed ineligible for such therapies in the opinion of the Investigator, the Investigator must document the reason the patient is considered ineligible",
                    "criterion": "ineligibility for therapies",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Patients must have a Karnofsky Performance Score (KPS) of greater than or equal to 70. Patients with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be considered eligible.",
            "criterions": [
                {
                    "exact_snippets": "Karnofsky Performance Score (KPS) of greater than or equal to 70",
                    "criterion": "Karnofsky Performance Score (KPS)",
                    "requirements": [
                        {
                            "requirement_type": "score",
                            "expected_value": {
                                "operator": ">=",
                                "value": 70,
                                "unit": "N/A"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "severe paraparesis/paraplegia",
                    "criterion": "paraparesis/paraplegia",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "severe"
                        }
                    ]
                },
                {
                    "exact_snippets": "need minimal assistance for self-care",
                    "criterion": "assistance for self-care",
                    "requirements": [
                        {
                            "requirement_type": "amount",
                            "expected_value": "minimal"
                        }
                    ]
                },
                {
                    "exact_snippets": "functionally independent",
                    "criterion": "functional independence",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Patients must not have received prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose of study drug (Cycle 1, Day 1); 42 days in the case of nitrosoureas; 42 days in the case of bevacizumab; 28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent; 14 days in the case of radiotherapy.",
            "criterions": [
                {
                    "exact_snippets": "Patients must not have received prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose of study drug",
                    "criterion": "prior cytotoxic chemotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "42 days in the case of nitrosoureas",
                    "criterion": "prior nitrosoureas",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 42,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "42 days in the case of bevacizumab",
                    "criterion": "prior bevacizumab",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 42,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent",
                    "criterion": "prior molecularly targeted agent",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        },
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 5,
                                        "unit": "half-lives"
                                    }
                                ]
                            }
                        },
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 14,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "14 days in the case of radiotherapy",
                    "criterion": "prior radiotherapy",
                    "requirements": [
                        {
                            "requirement_type": "time since last treatment",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 14,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Patients with AEs Grade ≥2 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have all their AEs resolved prior to the first dose of study drug (Cycle 1, Day 1), except for alopecia or neuropathy; Grade 1 or 2 lymphopenia is allowed.",
            "criterions": [
                {
                    "exact_snippets": "Patients with AEs Grade ≥2 related to prior therapies ... must have all their AEs resolved",
                    "criterion": "adverse events (AEs)",
                    "requirements": [
                        {
                            "requirement_type": "grade",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "N/A"
                            }
                        },
                        {
                            "requirement_type": "resolution",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "alopecia",
                    "criterion": "alopecia",
                    "requirements": [
                        {
                            "requirement_type": "resolution",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "neuropathy",
                    "criterion": "neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "resolution",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Grade 1 or 2 lymphopenia is allowed",
                    "criterion": "lymphopenia",
                    "requirements": [
                        {
                            "requirement_type": "grade",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "=",
                                        "value": 1,
                                        "unit": "N/A"
                                    },
                                    {
                                        "operator": "=",
                                        "value": 2,
                                        "unit": "N/A"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Patients must not have undergone major surgery 4 weeks prior to the first dose of study drug (Cycle 1, Day 1) and must have completely recovered from any surgery (minor surgical procedures such as skin biopsies and port placement done on an outpatient basis do not require a waiting period).",
            "criterions": [
                {
                    "exact_snippets": "Patients must not have undergone major surgery 4 weeks prior to the first dose of study drug",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "time since",
                            "expected_value": {
                                "operator": ">=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "must have completely recovered from any surgery",
                    "criterion": "recovery from surgery",
                    "requirements": [
                        {
                            "requirement_type": "recovery status",
                            "expected_value": "completely recovered"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Patients must have normal organ and marrow function as defined below:",
            "criterions": [
                {
                    "exact_snippets": "normal organ and marrow function",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "functionality",
                            "expected_value": "normal"
                        }
                    ]
                },
                {
                    "exact_snippets": "normal organ and marrow function",
                    "criterion": "marrow function",
                    "requirements": [
                        {
                            "requirement_type": "functionality",
                            "expected_value": "normal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count (ANC) ≥1,500/mcL.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count (ANC) ≥1,500/mcL.",
                    "criterion": "absolute neutrophil count (ANC)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelets ≥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": "* Hemoglobin ≥9.0 mg/dL without transfusion in 2 prior weeks.",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin ≥9.0 mg/dL",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9.0,
                                "unit": "mg/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "without transfusion in 2 prior weeks",
                    "criterion": "transfusion",
                    "requirements": [
                        {
                            "requirement_type": "absence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "2 prior weeks"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Total bilirubin ≤1.5 × upper limit of normal (ULN) (patients with Gilbert's syndrome may be included with total bilirubin >1.5 × ULN if direct bilirubin is ≤1.5 × ULN).",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin ≤1.5 × upper limit of normal (ULN)",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with Gilbert's syndrome may be included",
                    "criterion": "Gilbert's syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "total bilirubin >1.5 × ULN if direct bilirubin is ≤1.5 × ULN",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">",
                                "value": 1.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "direct bilirubin is ≤1.5 × ULN",
                    "criterion": "direct bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × ULN.",
            "criterions": [
                {
                    "exact_snippets": "Aspartate aminotransferase (AST) ... ≤2.5 × ULN",
                    "criterion": "aspartate aminotransferase (AST)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alanine aminotransferase (ALT) ≤2.5 × ULN",
                    "criterion": "alanine aminotransferase (ALT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "× ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Measured or estimated creatinine clearance (CLcr) ≥40 mL/minute for patients with creatinine levels above normal. CLcr will be calculated by the Cockcroft-Gault equation for renal function.",
            "criterions": [
                {
                    "exact_snippets": "Measured or estimated creatinine clearance (CLcr) ≥40 mL/minute",
                    "criterion": "creatinine clearance (CLcr)",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 40,
                                "unit": "mL/minute"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "patients with creatinine levels above normal",
                    "criterion": "creatinine levels",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": "above normal"
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Patients must provide a tumor specimen (paraffin-embedded block and/or frozen tissue) from a prior resection or biopsy available that is sufficient to perform biomarker assays, ≥15 unstained slides for immunohistochemistry (IHC) analysis must be received by the NOB by the first dose of study drug (Cycle 1, Day 1). For patients with ≥10 to <15 slides, eligibility will be reviewed on a case-by-case basis.",
            "criterions": [
                {
                    "exact_snippets": "Patients must provide a tumor specimen (paraffin-embedded block and/or frozen tissue) from a prior resection or biopsy available",
                    "criterion": "tumor specimen",
                    "requirements": [
                        {
                            "requirement_type": "availability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "sufficient to perform biomarker assays",
                    "criterion": "tumor specimen",
                    "requirements": [
                        {
                            "requirement_type": "sufficiency for biomarker assays",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "≥15 unstained slides for immunohistochemistry (IHC) analysis must be received by the NOB by the first dose of study drug (Cycle 1, Day 1)",
                    "criterion": "unstained slides for IHC analysis",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 15,
                                "unit": "slides"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "For patients with ≥10 to <15 slides, eligibility will be reviewed on a case-by-case basis",
                    "criterion": "unstained slides for IHC analysis",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 10,
                                        "unit": "slides"
                                    },
                                    {
                                        "operator": "<",
                                        "value": 15,
                                        "unit": "slides"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Dependent upon dose level assignment and drug formulation (i.e., capsules versus powder in bottle [PIB]), patients must be able to either swallow oral capsules or swallow liquids.",
            "criterions": [
                {
                    "exact_snippets": "patients must be able to either swallow oral capsules",
                    "criterion": "ability to swallow oral capsules",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must be able to ... swallow liquids",
                    "criterion": "ability to swallow liquids",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Patients must provide study-specific informed consent prior to enrollment. No Durable Power of Attorney or Next of Kin can provide initial consent.",
            "criterions": [
                {
                    "exact_snippets": "Patients must provide study-specific informed consent",
                    "criterion": "study-specific informed consent",
                    "requirements": [
                        {
                            "requirement_type": "provision",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "No Durable Power of Attorney or Next of Kin can provide initial consent",
                    "criterion": "initial consent",
                    "requirements": [
                        {
                            "requirement_type": "provision",
                            "expected_value": "Patients only"
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Patients must be able to tolerate a magnetic resonance imaging (MRI) study with intravenous gadolinium contrast.",
            "criterions": [
                {
                    "exact_snippets": "Patients must be able to tolerate a magnetic resonance imaging (MRI) study",
                    "criterion": "MRI study tolerance",
                    "requirements": [
                        {
                            "requirement_type": "tolerance",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "with intravenous gadolinium contrast",
                    "criterion": "intravenous gadolinium contrast tolerance",
                    "requirements": [
                        {
                            "requirement_type": "tolerance",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. Patients must have a negative COVID-19 test within 72 hours of the first dose of study drug (Cycle 1, Day 1). Patients who had documented COVID-19 infection within 90 days of treatment but more than 20 days from infection do not need to be tested.",
            "criterions": [
                {
                    "exact_snippets": "negative COVID-19 test within 72 hours of the first dose of study drug",
                    "criterion": "COVID-19 test result",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 72 hours of the first dose of study drug"
                        }
                    ]
                },
                {
                    "exact_snippets": "documented COVID-19 infection within 90 days of treatment but more than 20 days from infection",
                    "criterion": "COVID-19 infection history",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 90,
                                        "unit": "days"
                                    },
                                    {
                                        "operator": ">",
                                        "value": 20,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "Patients who meet any of the following criteria will be excluded from the study:",
            "criterions": [
                {
                    "exact_snippets": "Patients who meet any of the following criteria will be excluded from the study",
                    "criterion": "exclusion criteria",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206 (e.g., ONC201) or its excipients.",
            "criterions": [
                {
                    "exact_snippets": "history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206",
                    "criterion": "allergic reactions to similar compounds",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "history of allergic reactions attributed to ... its excipients",
                    "criterion": "allergic reactions to excipients",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.",
            "criterions": [
                {
                    "exact_snippets": "uncontrolled intercurrent illness",
                    "criterion": "intercurrent illness",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "ongoing or active infection",
                    "criterion": "infection",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": [
                                "ongoing",
                                "active"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "psychiatric illness/social situations that would limit compliance with study requirements",
                    "criterion": "psychiatric illness/social situations",
                    "requirements": [
                        {
                            "requirement_type": "impact on compliance",
                            "expected_value": "limit"
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Patients who are unable or unwilling to abide by the study protocol or cooperate fully with the Investigator.",
            "criterions": [
                {
                    "exact_snippets": "unable or unwilling to abide by the study protocol",
                    "criterion": "ability to abide by the study protocol",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unable or unwilling to ... cooperate fully with the Investigator",
                    "criterion": "ability to cooperate with the Investigator",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Patients with a known HIV-positive test on combination anti-retroviral therapy are ineligible for this initial first-in-human trial because of the potential for PK interactions with ONC206.",
            "criterions": [
                {
                    "exact_snippets": "known HIV-positive test",
                    "criterion": "HIV status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "combination anti-retroviral therapy",
                    "criterion": "anti-retroviral therapy",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": "combination anti-retroviral therapy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Patients with active cardiac disease, including any of the following:",
            "criterions": [
                {
                    "exact_snippets": "active cardiac disease",
                    "criterion": "cardiac disease",
                    "requirements": [
                        {
                            "requirement_type": "activity",
                            "expected_value": "active"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Corrected QT interval (QTc) ≥470 msec on screening electrocardiogram (ECG; using the QTc by Fridericia's [QTcF] formula);",
            "criterions": [
                {
                    "exact_snippets": "Corrected QT interval (QTc) ≥470 msec on screening electrocardiogram (ECG; using the QTc by Fridericia's [QTcF] formula)",
                    "criterion": "Corrected QT interval (QTc)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 470,
                                "unit": "msec"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Angina pectoris that requires the use of anti-anginal medication;",
            "criterions": [
                {
                    "exact_snippets": "Angina pectoris that requires the use of anti-anginal medication",
                    "criterion": "angina pectoris",
                    "requirements": [
                        {
                            "requirement_type": "medication requirement",
                            "expected_value": "anti-anginal medication"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Ventricular arrhythmias except for benign premature ventricular contractions;",
            "criterions": [
                {
                    "exact_snippets": "Ventricular arrhythmias except for benign premature ventricular contractions",
                    "criterion": "ventricular arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "exclusion",
                            "expected_value": [
                                "benign premature ventricular contractions"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;",
            "criterions": [
                {
                    "exact_snippets": "Supraventricular and nodal arrhythmias",
                    "criterion": "supraventricular and nodal arrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "requiring a pacemaker",
                    "criterion": "pacemaker requirement",
                    "requirements": [
                        {
                            "requirement_type": "necessity",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Conduction abnormality requiring a pacemaker;",
            "criterions": [
                {
                    "exact_snippets": "Conduction abnormality requiring a pacemaker",
                    "criterion": "conduction abnormality",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": "pacemaker"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Valvular disease with documented compromise in cardiac function; and/or",
            "criterions": [
                {
                    "exact_snippets": "Valvular disease with documented compromise in cardiac function",
                    "criterion": "valvular disease",
                    "requirements": [
                        {
                            "requirement_type": "compromise in cardiac function",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Symptomatic pericarditis.",
            "criterions": [
                {
                    "exact_snippets": "Symptomatic pericarditis",
                    "criterion": "pericarditis",
                    "requirements": [
                        {
                            "requirement_type": "symptomatic",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Patients with a history of cardiac dysfunction including any of the following:",
            "criterions": [
                {
                    "exact_snippets": "history of cardiac dysfunction",
                    "criterion": "cardiac dysfunction",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction function;",
            "criterions": [
                {
                    "exact_snippets": "Myocardial infarction within the last 6 months",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 6,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "documented by persistent elevated cardiac enzymes",
                    "criterion": "elevated cardiac enzymes",
                    "requirements": [
                        {
                            "requirement_type": "persistence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "persistent regional wall abnormalities on assessment of left ventricular ejection fraction function",
                    "criterion": "regional wall abnormalities",
                    "requirements": [
                        {
                            "requirement_type": "persistence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of documented congestive heart failure (New York Heart Association functional classification III-IV); and/or",
            "criterions": [
                {
                    "exact_snippets": "History of documented congestive heart failure (New York Heart Association functional classification III-IV)",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "classification",
                            "expected_value": [
                                "New York Heart Association functional classification III",
                                "New York Heart Association functional classification IV"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Documented cardiomyopathy.",
            "criterions": [
                {
                    "exact_snippets": "Documented cardiomyopathy",
                    "criterion": "cardiomyopathy",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Patients who have had an ischemic or hemorrhagic stroke in the last 3 months. If the patient has had a recent tumor resection, cerebral ischemic or hemorrhagic changes that occur peri operatively are not an exclusion.",
            "criterions": [
                {
                    "exact_snippets": "Patients who have had an ischemic or hemorrhagic stroke in the last 3 months",
                    "criterion": "stroke",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "ischemic",
                                "hemorrhagic"
                            ]
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 3,
                                        "unit": "months"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "recent tumor resection",
                    "criterion": "tumor resection",
                    "requirements": [
                        {
                            "requirement_type": "recency",
                            "expected_value": "recent"
                        }
                    ]
                },
                {
                    "exact_snippets": "cerebral ischemic or hemorrhagic changes that occur peri operatively are not an exclusion",
                    "criterion": "cerebral ischemic or hemorrhagic changes",
                    "requirements": [
                        {
                            "requirement_type": "context",
                            "expected_value": "peri operative"
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Patients with refractory epilepsy are excluded. Patients with primarily or secondarily generalized seizures in the 28 days prior to study enrollment will be excluded. Peri-operative seizures, defined as seizures occurring within the 7 days after a stereotactic biopsy, open biopsy, or surgical resection will not be an exclusion as long as the patient has had no generalized seizures starting 8 days after the surgical procedure. Patients with prior seizures must be on stable doses of 1 or 2 seizure medications for at least 14 days prior to study enrollment.",
            "criterions": [
                {
                    "exact_snippets": "Patients with refractory epilepsy are excluded.",
                    "criterion": "refractory epilepsy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with primarily or secondarily generalized seizures in the 28 days prior to study enrollment will be excluded.",
                    "criterion": "generalized seizures",
                    "requirements": [
                        {
                            "requirement_type": "occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 28,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Peri-operative seizures, defined as seizures occurring within the 7 days after a stereotactic biopsy, open biopsy, or surgical resection will not be an exclusion",
                    "criterion": "peri-operative seizures",
                    "requirements": [
                        {
                            "requirement_type": "occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": "<=",
                                        "value": 7,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "as long as the patient has had no generalized seizures starting 8 days after the surgical procedure.",
                    "criterion": "generalized seizures post-surgery",
                    "requirements": [
                        {
                            "requirement_type": "occurrence",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 8,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients with prior seizures must be on stable doses of 1 or 2 seizure medications for at least 14 days prior to study enrollment.",
                    "criterion": "seizure medication stability",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 14,
                                        "unit": "days"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC206 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).",
            "criterions": [
                {
                    "exact_snippets": "impairment of gastrointestinal (GI) function",
                    "criterion": "gastrointestinal function",
                    "requirements": [
                        {
                            "requirement_type": "impairment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "GI disease that may significantly alter the absorption of ONC206",
                    "criterion": "GI disease",
                    "requirements": [
                        {
                            "requirement_type": "impact on absorption of ONC206",
                            "expected_value": "significant alteration"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled nausea",
                    "criterion": "nausea",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled ... vomiting",
                    "criterion": "vomiting",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled ... diarrhea",
                    "criterion": "diarrhea",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "malabsorption syndrome",
                    "criterion": "malabsorption syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "small bowel resection",
                    "criterion": "small bowel resection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Patients who have been treated with any hematopoietic colony-stimulating growth factors (CSFs) (e.g., granulocyte-CSF, granulocyte-macrophage-CSF) ≤2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued.",
            "criterions": [
                {
                    "exact_snippets": "treated with any hematopoietic colony-stimulating growth factors (CSFs) (e.g., granulocyte-CSF, granulocyte-macrophage-CSF) ≤2 weeks prior to starting study drug",
                    "criterion": "treatment with hematopoietic colony-stimulating growth factors",
                    "requirements": [
                        {
                            "requirement_type": "time since treatment",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued",
                    "criterion": "erythropoietin or darbepoetin therapy",
                    "requirements": [
                        {
                            "requirement_type": "time since initiation",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin derivative anticoagulant.",
            "criterions": [
                {
                    "exact_snippets": "currently taking therapeutic doses of warfarin sodium",
                    "criterion": "warfarin sodium usage",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "currently taking therapeutic doses of ... any other coumadin derivative anticoagulant",
                    "criterion": "coumadin derivative anticoagulant usage",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Patients who are taking strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, 2D6, 1A2, 2C9, and 2C19 within at least 14 days prior to the first dose of study drug (Cycle 1, Day 1); these medications are excluded throughout the study.",
            "criterions": [
                {
                    "exact_snippets": "Patients who are taking strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, 2D6, 1A2, 2C9, and 2C19",
                    "criterion": "use of strong inhibitors or inducers of cytochrome P450 enzymes",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "within at least 14 days prior to the first dose of study drug (Cycle 1, Day 1)",
                    "criterion": "time since last use of strong inhibitors or inducers of cytochrome P450 enzymes",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Women who are pregnant or breast feeding.",
            "criterions": [
                {
                    "exact_snippets": "Women who are pregnant",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "breast feeding",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "15. Women of child-bearing potential with a positive serum pregnancy test ≤72 hours prior to the first dose of study drug (Cycle 1, Day 1).",
            "criterions": [
                {
                    "exact_snippets": "Women of child-bearing potential",
                    "criterion": "child-bearing potential",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "positive serum pregnancy test",
                    "criterion": "serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "positive"
                        }
                    ]
                },
                {
                    "exact_snippets": "≤72 hours prior to the first dose of study drug",
                    "criterion": "timing of serum pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 72,
                                "unit": "hours"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. Patients who are receiving concomitant standard and/or investigational anti-cancer therapy.",
            "criterions": [
                {
                    "exact_snippets": "Patients who are receiving concomitant standard and/or investigational anti-cancer therapy.",
                    "criterion": "concomitant anti-cancer therapy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "17. Patients with alcohol or substance abuse which, in the opinion of the Investigator, would interfere with compliance or safety.",
            "criterions": [
                {
                    "exact_snippets": "Patients with alcohol or substance abuse",
                    "criterion": "alcohol or substance abuse",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "in the opinion of the Investigator, would interfere with compliance",
                    "criterion": "interference with compliance",
                    "requirements": [
                        {
                            "requirement_type": "opinion",
                            "expected_value": "Investigator"
                        }
                    ]
                },
                {
                    "exact_snippets": "in the opinion of the Investigator, would interfere with ... safety",
                    "criterion": "interference with safety",
                    "requirements": [
                        {
                            "requirement_type": "opinion",
                            "expected_value": "Investigator"
                        }
                    ]
                }
            ]
        },
        {
            "line": "18. Patients with the presence of any other serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with patients' safety, obtaining informed consent or compliance to the study procedures as determined by the Investigators.",
            "criterions": [
                {
                    "exact_snippets": "presence of any other serious and/or unstable pre-existing medical disorder",
                    "criterion": "pre-existing medical disorder",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "stability",
                            "expected_value": "unstable"
                        },
                        {
                            "requirement_type": "severity",
                            "expected_value": "serious"
                        }
                    ]
                },
                {
                    "exact_snippets": "presence of any other ... psychiatric disorder",
                    "criterion": "psychiatric disorder",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "presence of any other ... conditions that could interfere with patients' safety, obtaining informed consent or compliance to the study procedures",
                    "criterion": "conditions interfering with study",
                    "requirements": [
                        {
                            "requirement_type": "interference",
                            "expected_value": [
                                "patients' safety",
                                "obtaining informed consent",
                                "compliance to the study procedures"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "19. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, or men who do not agree to use highly effective contraception during treatment and for 16 additional weeks after the final dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Women of childbearing potential, defined as all women physiologically capable of becoming pregnant",
                    "criterion": "women of childbearing potential",
                    "requirements": [
                        {
                            "requirement_type": "physiological capability",
                            "expected_value": "capable of becoming pregnant"
                        }
                    ]
                },
                {
                    "exact_snippets": "men who do not agree to use highly effective contraception during treatment and for 16 additional weeks after the final dose of study drug",
                    "criterion": "contraception use",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": false
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": "during treatment and for 16 additional weeks after the final dose of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Highly effective contraception is defined as either:",
            "criterions": [
                {
                    "exact_snippets": "Highly effective contraception",
                    "criterion": "contraception",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": "highly effective"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* True abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.",
            "criterions": [
                {
                    "exact_snippets": "True abstinence: When this is in line with the preferred and usual lifestyle of the patient.",
                    "criterion": "true abstinence",
                    "requirements": [
                        {
                            "requirement_type": "lifestyle alignment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.",
                    "criterion": "contraception methods",
                    "requirements": [
                        {
                            "requirement_type": "acceptability",
                            "expected_value": [
                                "calendar",
                                "ovulation",
                                "symptothermal",
                                "post-ovulation",
                                "withdrawal"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Sterilization: Females must have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.",
            "criterions": [
                {
                    "exact_snippets": "Females must have had surgical bilateral oophorectomy (with or without hysterectomy)",
                    "criterion": "surgical bilateral oophorectomy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "tubal ligation at least 6 weeks ago",
                    "criterion": "tubal ligation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time since procedure",
                            "expected_value": {
                                "operator": ">=",
                                "value": 6,
                                "unit": "weeks"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment",
                    "criterion": "reproductive status confirmation",
                    "requirements": [
                        {
                            "requirement_type": "confirmation method",
                            "expected_value": "follow up hormone level assessment"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.",
            "criterions": [
                {
                    "exact_snippets": "Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate)",
                    "criterion": "male partner sterilization",
                    "requirements": [
                        {
                            "requirement_type": "documentation",
                            "expected_value": "absence of sperm in the ejaculate"
                        }
                    ]
                },
                {
                    "exact_snippets": "For female patients on the study, the vasectomized male partner should be the sole partner for that patient",
                    "criterion": "vasectomized male partner",
                    "requirements": [
                        {
                            "requirement_type": "exclusivity",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* If patients are not practicing true abstinence and/or if the patient or sexual partner have not had a sterilization procedure as listed above, patients and their sexual partners must follow double barrier contraception in accordance with the guidelines for contraception below:",
            "criterions": [
                {
                    "exact_snippets": "patients are not practicing true abstinence",
                    "criterion": "abstinence",
                    "requirements": [
                        {
                            "requirement_type": "practice",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "patient or sexual partner have not had a sterilization procedure",
                    "criterion": "sterilization procedure",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "patients and their sexual partners must follow double barrier contraception",
                    "criterion": "contraception",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "double barrier"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Females of childbearing potential:",
            "criterions": [
                {
                    "exact_snippets": "Females of childbearing potential",
                    "criterion": "gender and reproductive potential",
                    "requirements": [
                        {
                            "requirement_type": "gender",
                            "expected_value": "female"
                        },
                        {
                            "requirement_type": "reproductive potential",
                            "expected_value": "childbearing potential"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Must use an intrauterine device or intrauterine system, during dosing of any study agent and for 16 weeks after final dose of study drug; or",
            "criterions": [
                {
                    "exact_snippets": "Must use an intrauterine device or intrauterine system, during dosing of any study agent and for 16 weeks after final dose of study drug",
                    "criterion": "contraceptive method",
                    "requirements": [
                        {
                            "requirement_type": "type",
                            "expected_value": [
                                "intrauterine device",
                                "intrauterine system"
                            ]
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": "during dosing of any study agent and for 16 weeks after final dose of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Must use a double barrier method of contraception: use of an occlusive cap (diaphragm or cervical/vault cap) with spermicide for women combined with use of a condom by their male partners capable of conceiving offspring.",
            "criterions": [
                {
                    "exact_snippets": "Must use a double barrier method of contraception: use of an occlusive cap (diaphragm or cervical/vault cap) with spermicide for women",
                    "criterion": "contraception method for women",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "double barrier method"
                        },
                        {
                            "requirement_type": "components",
                            "expected_value": [
                                "occlusive cap",
                                "spermicide"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "use of a condom by their male partners capable of conceiving offspring",
                    "criterion": "contraception method for male partners",
                    "requirements": [
                        {
                            "requirement_type": "method",
                            "expected_value": "condom"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Males capable of conceiving offspring must use condoms during dosing of study agent and for an additional 16 weeks after final dose of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Males capable of conceiving offspring",
                    "criterion": "male reproductive capability",
                    "requirements": [
                        {
                            "requirement_type": "capability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "must use condoms during dosing of study agent and for an additional 16 weeks after final dose of study drug",
                    "criterion": "condom use",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": "during dosing of study agent and for an additional 16 weeks after final dose of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Note: Oral, implantable, or injectable contraceptives may be affected by CYP interactions, and are therefore not considered effective for this study.",
            "criterions": [
                {
                    "exact_snippets": "Oral, implantable, or injectable contraceptives ... not considered effective for this study.",
                    "criterion": "contraceptive method",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "20. Previous receipt of ONC201, placebo, or blinded study drug from an ONC201 clinical study, or from any other source for H3 K27M-mutant diffuse glioma on or after 01 January 2023.",
            "criterions": [
                {
                    "exact_snippets": "Previous receipt of ONC201",
                    "criterion": "previous receipt of ONC201",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous receipt of ... placebo",
                    "criterion": "previous receipt of placebo",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Previous receipt of ... blinded study drug",
                    "criterion": "previous receipt of blinded study drug",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "H3 K27M-mutant diffuse glioma",
                    "criterion": "H3 K27M-mutant diffuse glioma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "on or after 01 January 2023",
                    "criterion": "date of receipt",
                    "requirements": [
                        {
                            "requirement_type": "date",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2023,
                                "unit": "year"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [
        {
            "line": "Patients must meet all the following criteria to participate in the study:",
            "criterions": []
        },
        {
            "line": "4. (Inclusion Criterion #4 was removed in Amendment 3.)",
            "criterions": []
        },
        {
            "line": "6. (Inclusion Criterion #6 was removed in Amendment 7.)",
            "criterions": []
        },
        {
            "line": "10. (Inclusion Criterion #10 was removed in Amendment 3)",
            "criterions": []
        },
        {
            "line": "15. (Inclusion Criterion #15 was removed in Amendment 6)",
            "criterions": []
        },
        {
            "line": "17. (Inclusion Criterion #17 was removed in Amendment 6)",
            "criterions": []
        }
    ],
    "failed_exclusion": [
        {
            "line": "1. (Exclusion Criterion #1 was removed in Amendment 3)",
            "criterions": []
        }
    ],
    "failed_miscellaneous": []
}