{
    "info": {
        "nct_id": "NCT04161391",
        "official_title": "A Phase 1/2 Study of TPX-0046, A Novel Oral RET/SRC Inhibitor in Adult Subjects With Advanced/Metastatic Solid Tumors Harboring Oncogenic RET Fusions or Mutations",
        "inclusion_criteria": "1. Age ≥ 18 (or age ≥ 20 as required by local regulation).\n2. Histological or cytological confirmation of advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations, who either have disease progression on, or are intolerant to standard therapy; OR are ineligible for standard therapy or for whom no standard therapy exists; OR are unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the Investigator OR have declined standard therapy.\n3. ECOG performance status ≤ 1.\n4. Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria).\n5. Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the study if they meet protocol specified criteria.\n6. Adequate organ function.\n7. Life expectancy ≥ 12 weeks.\nHealthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "1. Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.\n2. Presence or history of any other primary malignancy within 3 years other than a history of adequately treated basal or squamous cell carcinoma of the skin, or any adequately treated in situ carcinoma.\n3. Major surgery within four weeks of the start of therapy.\n4. Clinically significant cardiovascular disease (either active or within six months before enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2.\n5. Any of the following cardiac criteria:\n\n   * Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value\n   * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)\n   * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval\n6. Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).\n7. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.\n8. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.\n9. Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.",
        "miscellaneous_criteria": ""
    },
    "inclusion_lines": [
        {
            "line": "1. Age ≥ 18 (or age ≥ 20 as required by local regulation).",
            "criterions": [
                {
                    "exact_snippets": "Age ≥ 18",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "age ≥ 20 as required by local regulation",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum age",
                            "expected_value": {
                                "operator": ">=",
                                "value": 20,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Histological or cytological confirmation of advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations, who either have disease progression on, or are intolerant to standard therapy; OR are ineligible for standard therapy or for whom no standard therapy exists; OR are unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the Investigator OR have declined standard therapy.",
            "criterions": [
                {
                    "exact_snippets": "Histological or cytological confirmation of advanced/metastatic solid tumors",
                    "criterion": "advanced/metastatic solid tumors",
                    "requirements": [
                        {
                            "requirement_type": "confirmation",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "harboring oncogenic RET fusions or mutations",
                    "criterion": "oncogenic RET fusions or mutations",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "disease progression on, or are intolerant to standard therapy",
                    "criterion": "standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "disease progression or intolerance",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "ineligible for standard therapy",
                    "criterion": "standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "no standard therapy exists",
                    "criterion": "standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "existence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the Investigator",
                    "criterion": "standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "tolerance or benefit",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "have declined standard therapy",
                    "criterion": "standard therapy",
                    "requirements": [
                        {
                            "requirement_type": "acceptance",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. ECOG performance status ≤ 1.",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status ≤ 1",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "performance status",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1,
                                "unit": "N/A"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria).",
            "criterions": [
                {
                    "exact_snippets": "Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria)",
                    "criterion": "measurable or evaluable disease",
                    "requirements": [
                        {
                            "requirement_type": "existence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "evaluation criteria",
                            "expected_value": "RECIST v1.1"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the study if they meet protocol specified criteria.",
            "criterions": [
                {
                    "exact_snippets": "asymptomatic primary CNS tumors",
                    "criterion": "primary CNS tumors",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "asymptomatic"
                        }
                    ]
                },
                {
                    "exact_snippets": "asymptomatic ... brain metastases",
                    "criterion": "brain metastases",
                    "requirements": [
                        {
                            "requirement_type": "symptoms",
                            "expected_value": "asymptomatic"
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Adequate organ function.",
            "criterions": [
                {
                    "exact_snippets": "Adequate organ function.",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Life expectancy ≥ 12 weeks.",
            "criterions": [
                {
                    "exact_snippets": "Life expectancy ≥ 12 weeks.",
                    "criterion": "life expectancy",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 12,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "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": "1. Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.",
            "criterions": [
                {
                    "exact_snippets": "Locally advanced solid tumor",
                    "criterion": "solid tumor",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "locally advanced"
                        }
                    ]
                },
                {
                    "exact_snippets": "candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy",
                    "criterion": "curative treatment",
                    "requirements": [
                        {
                            "requirement_type": "eligibility",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Presence or history of any other primary malignancy within 3 years other than a history of adequately treated basal or squamous cell carcinoma of the skin, or any adequately treated in situ carcinoma.",
            "criterions": [
                {
                    "exact_snippets": "Presence or history of any other primary malignancy within 3 years",
                    "criterion": "primary malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "time frame",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "other than a history of adequately treated basal or squamous cell carcinoma of the skin",
                    "criterion": "basal or squamous cell carcinoma of the skin",
                    "requirements": [
                        {
                            "requirement_type": "treatment adequacy",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "any adequately treated in situ carcinoma",
                    "criterion": "in situ carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "treatment adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Major surgery within four weeks of the start of therapy.",
            "criterions": [
                {
                    "exact_snippets": "Major surgery within four weeks of the start of therapy.",
                    "criterion": "major surgery",
                    "requirements": [
                        {
                            "requirement_type": "time since surgery",
                            "expected_value": {
                                "operator": "<=",
                                "value": 4,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Clinically significant cardiovascular disease (either active or within six months before enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2.",
            "criterions": [
                {
                    "exact_snippets": "Clinically significant cardiovascular disease (either active or within six months before enrollment)",
                    "criterion": "clinically significant cardiovascular disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "myocardial infarction",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "unstable angina",
                    "criterion": "unstable angina",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "coronary/peripheral artery bypass graft",
                    "criterion": "coronary/peripheral artery bypass graft",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II)",
                    "criterion": "symptomatic congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "New York Heart Association Classification Class"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "cerebrovascular accident",
                    "criterion": "cerebrovascular accident",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "transient ischemic attack",
                    "criterion": "transient ischemic attack",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "symptomatic bradycardia",
                    "criterion": "symptomatic bradycardia",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "requirement for anti-arrhythmic medication",
                    "criterion": "requirement for anti-arrhythmic medication",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2",
                    "criterion": "ongoing cardiac dysrhythmias",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "CTCAE version 5.0 grade"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Any of the following cardiac criteria:",
            "criterions": [
                {
                    "exact_snippets": "Any of the following cardiac criteria",
                    "criterion": "cardiac criteria",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)",
            "criterions": [
                {
                    "exact_snippets": "clinically important abnormalities in rhythm",
                    "criterion": "ECG rhythm",
                    "requirements": [
                        {
                            "requirement_type": "abnormality",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "clinically important abnormalities in ... conduction",
                    "criterion": "ECG conduction",
                    "requirements": [
                        {
                            "requirement_type": "abnormality",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "clinically important abnormalities in ... morphology of resting ECG",
                    "criterion": "ECG morphology",
                    "requirements": [
                        {
                            "requirement_type": "abnormality",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "complete left bundle branch block",
                    "criterion": "left bundle branch block",
                    "requirements": [
                        {
                            "requirement_type": "completeness",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "third degree heart block",
                    "criterion": "heart block",
                    "requirements": [
                        {
                            "requirement_type": "degree",
                            "expected_value": "third"
                        }
                    ]
                },
                {
                    "exact_snippets": "second degree heart block",
                    "criterion": "heart block",
                    "requirements": [
                        {
                            "requirement_type": "degree",
                            "expected_value": "second"
                        }
                    ]
                },
                {
                    "exact_snippets": "PR interval > 250 msec",
                    "criterion": "PR interval",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">",
                                "value": 250,
                                "unit": "msec"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval",
            "criterions": [
                {
                    "exact_snippets": "factors that increase the risk of QTc prolongation",
                    "criterion": "risk of QTc prolongation",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "risk of arrhythmic events",
                    "criterion": "risk of arrhythmic events",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "heart failure",
                    "criterion": "heart failure",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "congenital long QT syndrome",
                    "criterion": "congenital long QT syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "family history of long QT syndrome",
                    "criterion": "family history of long QT syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "concomitant medication known to prolong the QT interval",
                    "criterion": "concomitant medication known to prolong the QT interval",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).",
            "criterions": [
                {
                    "exact_snippets": "clinically significant active infections",
                    "criterion": "active infections",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": "clinically significant"
                        },
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "bacterial",
                    "criterion": "bacterial infection",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "fungal",
                    "criterion": "fungal infection",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "viral",
                    "criterion": "viral infection",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "HIV positivity",
                    "criterion": "HIV infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.",
            "criterions": [
                {
                    "exact_snippets": "Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome)",
                    "criterion": "gastrointestinal disease",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "malabsorption syndromes that would impact drug absorption",
                    "criterion": "malabsorption syndromes",
                    "requirements": [
                        {
                            "requirement_type": "impact on drug absorption",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.",
            "criterions": [
                {
                    "exact_snippets": "Subjects being treated with ... strong CYP3A4 inhibitors",
                    "criterion": "treatment with strong CYP3A4 inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "anticipating the need for treatment with strong CYP3A4 inhibitors",
                    "criterion": "anticipated treatment with strong CYP3A4 inhibitors",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Subjects being treated with ... strong CYP3A4 ... inducers",
                    "criterion": "treatment with strong CYP3A4 inducers",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "anticipating the need for treatment with strong CYP3A4 ... inducers",
                    "criterion": "anticipated treatment with strong CYP3A4 inducers",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.",
            "criterions": [
                {
                    "exact_snippets": "current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices",
                    "criterion": "need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        }
    ],
    "miscellaneous_lines": [],
    "failed_inclusion": [],
    "failed_exclusion": [
        {
            "line": "* Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value",
            "criterions": [
                {
                    "exact_snippets": "Mean resting corrected QT interval ... QTc > 470 msec",
                    "criterion": "corrected QT interval",
                    "requirements": [
                        {
                            "requirement_type": "mean value",
                            "expected_value": {
                                "operator": ">",
                                "value": 470,
                                "unit": "msec"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "failed_miscellaneous": []
}