{
    "info": {
        "nct_id": "NCT05691491",
        "official_title": "A Phase 1/2 Trial Evaluating the Combination of Temozolomide and the Ataxia Telangiectasia and Rad3-Related Inhibitor M1774",
        "inclusion_criteria": "* Patients must have histologically or cytologically confirmed diagnosis of metastatic advanced cancer.\n* In dose escalation, any solid tumor patients with either O6-methylguanine DNA methyltransferase (MGMT) promoter hypermethylation positivity on testing / pre-screening of archival tissue OR an extracranial solid tumor where TMZ is considered a standard of care per National Comprehensive Cancer Network (NCCN) guidelines (neuroendocrine tumor, small cell lung cancer, melanoma or soft tissue sarcoma). The tumor lesion must be safely accessible to a mandatory biopsy. Patients with MGMT promoter hypermethylated colorectal cancer must be mismatch repair proficient / microsatellite stable.\n* In phase 2, only patients with mismatch repair proficient / microsatellite stable colorectal cancer that have MGMT promoter hypermethylation positivity on pre-screening of archival tissue will be eligible.\n* In dose escalation, patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. Patients may not have previously received temozolomide or an ataxia telangiectasia and rad3-related (ATR) inhibitor.\n* For patients with mismatch repair proficient / microsatellite stable colorectal cancer in the phase 2 portion, patients must have received prior therapy with 1 or more systemic therapies in the metastatic setting that includes 5-fluorouracil, irinotecan, and oxaliplatin. Patients with microsatellite stable colorectal cancer (mCRC) need to have had exposure, unless contraindicated, to all 3 of oxaliplatin, irinotecan, and fluoropyrimidine (FP).\n\nThe use of 5-fluorouracil and oxaliplatin in the adjuvant setting is acceptable, provided the development of metastatic disease was less than 6 months after the completion of adjuvant therapy.\n\nPatients with a prior hypersensitivity reaction to oxaliplatin in the adjuvant setting do not require retreatment in the metastatic setting.\n\n* Age >=18 years. Because no dosing or adverse event data are currently available on the use of M1774 in combination with temozolomide in patients < 18 years of age, children are excluded from this study.\n* Measurable disease on CT and/or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.\n* Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%).\n* Hemoglobin >=10 g/dL (No blood transfusions are allowed within 14 days of cycle 1 day 1 [C1D1]).\n* White blood cells (WBC) > 3 x 10^9/L.\n* Absolute neutrophil count >= 1,500/mcL.\n* Platelets >= 100,000/mcL.\n* Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).\n* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine-aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3 x institutional ULN except for when liver metastases are present, in which case they must be =< 5 x institutional ULN.\n* Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2.\n* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.\n* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.\n* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.\n* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for 4 weeks.\n* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.\n* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.\n* The effects of M1774 on the developing human fetus are unknown. For this reason and because ATR inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of M1774 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of M1774 administration.\n* Ability to understand and the willingness to sign a written informed consent document.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy, which may be =< grade 2.\n* History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to M1774 or temozolomide, including dacarbazine.\n* Patients with uncontrolled intercurrent illness.\n* Pregnant women are excluded from this study because M1774 is an ATR inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M1774 breastfeeding should be discontinued if the mother is treated with M1774. These potential risks also apply to temozolomide.\n* Patients with a prior history of ataxia telangiectasia.\n* Patients who are not able to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication.\n* Patients who cannot discontinue proton-pump inhibitors (PPIs) while taking M1774. H-2 receptor antagonists are allowed but should not be taken within 12 hours before or 2 hours after M1774. Antacids are also allowed, but should not be taken 2 hours before 2 hours after M1774.\n* Extensive RT involving greater than 30% of the bone marrow is not permitted during the study.\n* A Fridericia's correction formula (QTcF) > 480 ms is exclusionary given the potential for QT.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "* Patients must have histologically or cytologically confirmed diagnosis of metastatic advanced cancer.",
            "criterions": [
                {
                    "exact_snippets": "histologically or cytologically confirmed diagnosis",
                    "criterion": "diagnosis confirmation method",
                    "requirements": [
                        {
                            "requirement_type": "methods",
                            "expected_value": [
                                "histologically",
                                "cytologically"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "metastatic advanced cancer",
                    "criterion": "cancer stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "metastatic advanced"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* In dose escalation, any solid tumor patients with either O6-methylguanine DNA methyltransferase (MGMT) promoter hypermethylation positivity on testing / pre-screening of archival tissue OR an extracranial solid tumor where TMZ is considered a standard of care per National Comprehensive Cancer Network (NCCN) guidelines (neuroendocrine tumor, small cell lung cancer, melanoma or soft tissue sarcoma). The tumor lesion must be safely accessible to a mandatory biopsy. Patients with MGMT promoter hypermethylated colorectal cancer must be mismatch repair proficient / microsatellite stable.",
            "criterions": [
                {
                    "exact_snippets": "solid tumor patients",
                    "criterion": "solid tumor",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "O6-methylguanine DNA methyltransferase (MGMT) promoter hypermethylation positivity",
                    "criterion": "MGMT promoter hypermethylation",
                    "requirements": [
                        {
                            "requirement_type": "positivity",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "extracranial solid tumor",
                    "criterion": "extracranial solid tumor",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "TMZ is considered a standard of care per National Comprehensive Cancer Network (NCCN) guidelines",
                    "criterion": "TMZ standard of care",
                    "requirements": [
                        {
                            "requirement_type": "guideline",
                            "expected_value": "NCCN"
                        }
                    ]
                },
                {
                    "exact_snippets": "neuroendocrine tumor",
                    "criterion": "neuroendocrine tumor",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "small cell lung cancer",
                    "criterion": "small cell lung cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "melanoma",
                    "criterion": "melanoma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "soft tissue sarcoma",
                    "criterion": "soft tissue sarcoma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "tumor lesion must be safely accessible to a mandatory biopsy",
                    "criterion": "tumor lesion accessibility",
                    "requirements": [
                        {
                            "requirement_type": "biopsy accessibility",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "MGMT promoter hypermethylated colorectal cancer",
                    "criterion": "MGMT promoter hypermethylated colorectal cancer",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "mismatch repair proficient / microsatellite stable",
                    "criterion": "mismatch repair proficiency / microsatellite stability",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "proficient / stable"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* In phase 2, only patients with mismatch repair proficient / microsatellite stable colorectal cancer that have MGMT promoter hypermethylation positivity on pre-screening of archival tissue will be eligible.",
            "criterions": [
                {
                    "exact_snippets": "mismatch repair proficient / microsatellite stable colorectal cancer",
                    "criterion": "mismatch repair status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "proficient / microsatellite stable"
                        }
                    ]
                },
                {
                    "exact_snippets": "MGMT promoter hypermethylation positivity",
                    "criterion": "MGMT promoter hypermethylation",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "positivity"
                        }
                    ]
                },
                {
                    "exact_snippets": "pre-screening of archival tissue",
                    "criterion": "archival tissue",
                    "requirements": [
                        {
                            "requirement_type": "pre-screening",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* In dose escalation, patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. Patients may not have previously received temozolomide or an ataxia telangiectasia and rad3-related (ATR) inhibitor.",
            "criterions": [
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease",
                    "criterion": "progression after treatment",
                    "requirements": [
                        {
                            "requirement_type": "progression",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease",
                    "criterion": "treatment with all available therapies",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease",
                    "criterion": "treatment with immunotherapies",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease that are known to confer clinical benefit",
                    "criterion": "therapies known to confer clinical benefit",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease ... or are intolerant to treatment",
                    "criterion": "intolerance to treatment",
                    "requirements": [
                        {
                            "requirement_type": "intolerance",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease ... or refuse standard treatment",
                    "criterion": "refusal of standard treatment",
                    "requirements": [
                        {
                            "requirement_type": "refusal",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients may not have previously received temozolomide",
                    "criterion": "previous receipt of temozolomide",
                    "requirements": [
                        {
                            "requirement_type": "receipt",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Patients may not have previously received ... an ataxia telangiectasia and rad3-related (ATR) inhibitor",
                    "criterion": "previous receipt of ATR inhibitor",
                    "requirements": [
                        {
                            "requirement_type": "receipt",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* For patients with mismatch repair proficient / microsatellite stable colorectal cancer in the phase 2 portion, patients must have received prior therapy with 1 or more systemic therapies in the metastatic setting that includes 5-fluorouracil, irinotecan, and oxaliplatin. Patients with microsatellite stable colorectal cancer (mCRC) need to have had exposure, unless contraindicated, to all 3 of oxaliplatin, irinotecan, and fluoropyrimidine (FP).",
            "criterions": [
                {
                    "exact_snippets": "mismatch repair proficient / microsatellite stable colorectal cancer",
                    "criterion": "mismatch repair status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "proficient / stable"
                        }
                    ]
                },
                {
                    "exact_snippets": "received prior therapy with 1 or more systemic therapies in the metastatic setting",
                    "criterion": "prior therapy",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1,
                                "unit": "systemic therapies"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "includes 5-fluorouracil, irinotecan, and oxaliplatin",
                    "criterion": "prior therapy components",
                    "requirements": [
                        {
                            "requirement_type": "inclusion",
                            "expected_value": [
                                "5-fluorouracil",
                                "irinotecan",
                                "oxaliplatin"
                            ]
                        }
                    ]
                },
                {
                    "exact_snippets": "microsatellite stable colorectal cancer (mCRC)",
                    "criterion": "microsatellite stability",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "stable"
                        }
                    ]
                },
                {
                    "exact_snippets": "exposure, unless contraindicated, to all 3 of oxaliplatin, irinotecan, and fluoropyrimidine (FP)",
                    "criterion": "prior therapy exposure",
                    "requirements": [
                        {
                            "requirement_type": "inclusion",
                            "expected_value": [
                                "oxaliplatin",
                                "irinotecan",
                                "fluoropyrimidine"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "The use of 5-fluorouracil and oxaliplatin in the adjuvant setting is acceptable, provided the development of metastatic disease was less than 6 months after the completion of adjuvant therapy.",
            "criterions": [
                {
                    "exact_snippets": "The use of 5-fluorouracil and oxaliplatin in the adjuvant setting is acceptable",
                    "criterion": "use of 5-fluorouracil and oxaliplatin in the adjuvant setting",
                    "requirements": [
                        {
                            "requirement_type": "acceptability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "provided the development of metastatic disease was less than 6 months after the completion of adjuvant therapy",
                    "criterion": "development of metastatic disease",
                    "requirements": [
                        {
                            "requirement_type": "time since completion of adjuvant therapy",
                            "expected_value": {
                                "operator": "<",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "Patients with a prior hypersensitivity reaction to oxaliplatin in the adjuvant setting do not require retreatment in the metastatic setting.",
            "criterions": [
                {
                    "exact_snippets": "prior hypersensitivity reaction to oxaliplatin",
                    "criterion": "hypersensitivity reaction to oxaliplatin",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Age >=18 years. Because no dosing or adverse event data are currently available on the use of M1774 in combination with temozolomide in patients < 18 years of age, children are excluded from this study.",
            "criterions": [
                {
                    "exact_snippets": "Age >=18 years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Measurable disease on CT and/or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.",
            "criterions": [
                {
                    "exact_snippets": "Measurable disease on CT and/or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.",
                    "criterion": "measurable disease",
                    "requirements": [
                        {
                            "requirement_type": "evaluation method",
                            "expected_value": [
                                "CT",
                                "MRI"
                            ]
                        },
                        {
                            "requirement_type": "evaluation criteria",
                            "expected_value": "RECIST v1.1"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%).",
            "criterions": [
                {
                    "exact_snippets": "Eastern Cooperative Oncology Group (ECOG) performance status =< 2",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "performance status",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "N/A"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Karnofsky >= 60%",
                    "criterion": "Karnofsky performance status",
                    "requirements": [
                        {
                            "requirement_type": "performance status",
                            "expected_value": {
                                "operator": ">=",
                                "value": 60,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Hemoglobin >=10 g/dL (No blood transfusions are allowed within 14 days of cycle 1 day 1 [C1D1]).",
            "criterions": [
                {
                    "exact_snippets": "Hemoglobin >=10 g/dL",
                    "criterion": "hemoglobin level",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 10,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "No blood transfusions are allowed within 14 days of cycle 1 day 1 [C1D1]",
                    "criterion": "blood transfusions",
                    "requirements": [
                        {
                            "requirement_type": "time since last transfusion",
                            "expected_value": {
                                "operator": ">=",
                                "value": 14,
                                "unit": "days"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* White blood cells (WBC) > 3 x 10^9/L.",
            "criterions": [
                {
                    "exact_snippets": "White blood cells (WBC) > 3 x 10^9/L",
                    "criterion": "white blood cells (WBC)",
                    "requirements": [
                        {
                            "requirement_type": "count",
                            "expected_value": {
                                "operator": ">",
                                "value": 3,
                                "unit": "x 10^9/L"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Absolute neutrophil count >= 1,500/mcL.",
            "criterions": [
                {
                    "exact_snippets": "Absolute neutrophil count >= 1,500/mcL.",
                    "criterion": "absolute neutrophil count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1500,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Platelets >= 100,000/mcL.",
            "criterions": [
                {
                    "exact_snippets": "Platelets >= 100,000/mcL.",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 100000,
                                "unit": "mcL"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).",
            "criterions": [
                {
                    "exact_snippets": "Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x institutional upper limit of normal (ULN)"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine-aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3 x institutional ULN except for when liver metastases are present, in which case they must be =< 5 x institutional ULN.",
            "criterions": [
                {
                    "exact_snippets": "Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ... =< 3 x institutional ULN",
                    "criterion": "aspartate aminotransferase (AST)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "x institutional ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alanine-aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ... =< 3 x institutional ULN",
                    "criterion": "alanine-aminotransferase (ALT)",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "x institutional ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "liver metastases are present ... AST ... =< 5 x institutional ULN",
                    "criterion": "aspartate aminotransferase (AST) with liver metastases",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "x institutional ULN"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "liver metastases are present ... ALT ... =< 5 x institutional ULN",
                    "criterion": "alanine-aminotransferase (ALT) with liver metastases",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 5,
                                "unit": "x institutional ULN"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2.",
            "criterions": [
                {
                    "exact_snippets": "Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2.",
                    "criterion": "glomerular filtration rate (GFR)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 60,
                                "unit": "mL/min/1.73 m^2"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.",
            "criterions": [
                {
                    "exact_snippets": "Human immunodeficiency virus (HIV)-infected patients",
                    "criterion": "HIV infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "on effective anti-retroviral therapy",
                    "criterion": "anti-retroviral therapy",
                    "requirements": [
                        {
                            "requirement_type": "effectiveness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "undetectable viral load within 6 months",
                    "criterion": "viral load",
                    "requirements": [
                        {
                            "requirement_type": "detectability",
                            "expected_value": false
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": "within 6 months"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.",
            "criterions": [
                {
                    "exact_snippets": "evidence of chronic hepatitis B virus (HBV) infection",
                    "criterion": "chronic hepatitis B virus (HBV) infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "HBV viral load must be undetectable",
                    "criterion": "HBV viral load",
                    "requirements": [
                        {
                            "requirement_type": "detectability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "on suppressive therapy, if indicated",
                    "criterion": "suppressive therapy",
                    "requirements": [
                        {
                            "requirement_type": "indication",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.",
            "criterions": [
                {
                    "exact_snippets": "history of hepatitis C virus (HCV) infection must have been treated and cured",
                    "criterion": "history of hepatitis C virus (HCV) infection",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "treated and cured"
                        }
                    ]
                },
                {
                    "exact_snippets": "HCV infection who are currently on treatment ... undetectable HCV viral load",
                    "criterion": "HCV infection",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "currently on treatment"
                        },
                        {
                            "requirement_type": "viral load",
                            "expected_value": "undetectable"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for 4 weeks.",
            "criterions": [
                {
                    "exact_snippets": "treated brain metastases",
                    "criterion": "brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "treatment",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "follow-up brain imaging ... shows no evidence of progression for 4 weeks",
                    "criterion": "brain metastases progression",
                    "requirements": [
                        {
                            "requirement_type": "progression",
                            "expected_value": false
                        },
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.",
            "criterions": [
                {
                    "exact_snippets": "prior or concurrent malignancy",
                    "criterion": "malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "natural history or treatment does not have the potential to interfere with the safety or efficacy assessment",
                    "criterion": "interference with safety or efficacy assessment",
                    "requirements": [
                        {
                            "requirement_type": "potential to interfere",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.",
            "criterions": [
                {
                    "exact_snippets": "known history or current symptoms of cardiac disease",
                    "criterion": "cardiac disease",
                    "requirements": [
                        {
                            "requirement_type": "history or symptoms",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "history of treatment with cardiotoxic agents",
                    "criterion": "treatment with cardiotoxic agents",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "clinical risk assessment of cardiac function using the New York Heart Association Functional Classification ... class 2B or better",
                    "criterion": "New York Heart Association Functional Classification",
                    "requirements": [
                        {
                            "requirement_type": "classification",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2.5,
                                "unit": "class"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* The effects of M1774 on the developing human fetus are unknown. For this reason and because ATR inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of M1774 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of M1774 administration.",
            "criterions": [
                {
                    "exact_snippets": "women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence)",
                    "criterion": "contraception use for women",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Men treated or enrolled on this protocol must also agree to use adequate contraception",
                    "criterion": "contraception use for men",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Ability to understand and the willingness to sign a written informed consent document.",
            "criterions": [
                {
                    "exact_snippets": "Ability to understand",
                    "criterion": "ability to understand",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "willingness to sign a written informed consent document",
                    "criterion": "willingness to sign informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [
        {
            "line": "* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy, which may be =< grade 2.",
            "criterions": [
                {
                    "exact_snippets": "Patients who have not recovered from adverse events due to prior anti-cancer therapy ... have residual toxicities > grade 1",
                    "criterion": "recovery from adverse events",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 1,
                                "unit": "grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "alopecia ... may be =< grade 2",
                    "criterion": "alopecia",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "neuropathy ... may be =< grade 2",
                    "criterion": "neuropathy",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": "<=",
                                "value": 2,
                                "unit": "grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to M1774 or temozolomide, including dacarbazine.",
            "criterions": [
                {
                    "exact_snippets": "History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to M1774 or temozolomide, including dacarbazine.",
                    "criterion": "allergic reactions or hypersensitivity",
                    "requirements": [
                        {
                            "requirement_type": "attribution",
                            "expected_value": "compounds of similar chemical or biologic composition to M1774 or temozolomide, including dacarbazine"
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with uncontrolled intercurrent illness.",
            "criterions": [
                {
                    "exact_snippets": "uncontrolled intercurrent illness",
                    "criterion": "intercurrent illness",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Pregnant women are excluded from this study because M1774 is an ATR inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M1774 breastfeeding should be discontinued if the mother is treated with M1774. These potential risks also apply to temozolomide.",
            "criterions": [
                {
                    "exact_snippets": "Pregnant women are excluded",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "breastfeeding should be discontinued if the mother is treated with M1774",
                    "criterion": "breastfeeding",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients with a prior history of ataxia telangiectasia.",
            "criterions": [
                {
                    "exact_snippets": "prior history of ataxia telangiectasia",
                    "criterion": "ataxia telangiectasia",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients who are not able to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication.",
            "criterions": [
                {
                    "exact_snippets": "Patients who are not able to swallow orally administered medication",
                    "criterion": "ability to swallow orally administered medication",
                    "requirements": [
                        {
                            "requirement_type": "ability",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "gastrointestinal disorders likely to interfere with absorption of the study medication",
                    "criterion": "gastrointestinal disorders",
                    "requirements": [
                        {
                            "requirement_type": "interference with absorption of the study medication",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Patients who cannot discontinue proton-pump inhibitors (PPIs) while taking M1774. H-2 receptor antagonists are allowed but should not be taken within 12 hours before or 2 hours after M1774. Antacids are also allowed, but should not be taken 2 hours before 2 hours after M1774.",
            "criterions": [
                {
                    "exact_snippets": "Patients who cannot discontinue proton-pump inhibitors (PPIs) while taking M1774.",
                    "criterion": "proton-pump inhibitors (PPIs)",
                    "requirements": [
                        {
                            "requirement_type": "discontinuation",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "H-2 receptor antagonists are allowed but should not be taken within 12 hours before or 2 hours after M1774.",
                    "criterion": "H-2 receptor antagonists",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 12,
                                        "unit": "hours before"
                                    },
                                    {
                                        "operator": ">=",
                                        "value": 2,
                                        "unit": "hours after"
                                    }
                                ]
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Antacids are also allowed, but should not be taken 2 hours before 2 hours after M1774.",
                    "criterion": "antacids",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": {
                                "comparisons": [
                                    {
                                        "operator": ">=",
                                        "value": 2,
                                        "unit": "hours before"
                                    },
                                    {
                                        "operator": ">=",
                                        "value": 2,
                                        "unit": "hours after"
                                    }
                                ]
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Extensive RT involving greater than 30% of the bone marrow is not permitted during the study.",
            "criterions": [
                {
                    "exact_snippets": "Extensive RT involving greater than 30% of the bone marrow is not permitted",
                    "criterion": "extensive RT involving bone marrow",
                    "requirements": [
                        {
                            "requirement_type": "extent",
                            "expected_value": {
                                "operator": ">",
                                "value": 30,
                                "unit": "%"
                            }
                        },
                        {
                            "requirement_type": "permitted",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "* A Fridericia's correction formula (QTcF) > 480 ms is exclusionary given the potential for QT.",
            "criterions": [
                {
                    "exact_snippets": "Fridericia's correction formula (QTcF) > 480 ms",
                    "criterion": "QTcF",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">",
                                "value": 480,
                                "unit": "ms"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": []
}