Advancing Brigatinib Properties in ALK+ NSCLC Patients by Deep Phenotyping

Exclusion Criteria

• •1. History or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
• •2. Uncontrolled hypertension, defined as hypertension treated\* with anti-hypertensive drugs AND blood pressure ≥ 160 mmHg (systolic) or ≥ 100 mmHg (diastolic) in repeated measurements. Untreated elevated blood pressure is not an exclusion criterion and should receive adequate anti-hypertensive adjustment.
• •\*Please notecase of treatment, at least 3 anti-hypertensive drugs should have been used with the intention to control hypertensive disease
• •3. Systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers or treatment with any investigational systemic anticancer agents, chemotherapy or radiation therapy (except for stereotactic radiosurgery or stereotactic radiation therapy or palliative radiotherapy) within 14 days of randomization
• •4. Treatment with antineoplastic monoclonal antibodies within 30 days of randomization
• •5. Major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
• •6. Current symptomatic spinal cord compression as confirmed by radiographic imaging. Patients with leptomeningeal disease without symptomatic cord compression are allowed.
• •7. Significant or uncontrolled cardiovascular disease, defined as to the following:
• •* If an acute myocardial infarction has ensued in the past 6 months, successful reperfusion has to be documented and the patient has to be free of symptoms
• •* New York Heart Association Class III or IV heart failure (i.e. marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest) within 6 months prior to randomization
• •* Any history of clinically significant ventricular arrhythmia, defined as ventricular tachycardia (VT), ventricular fibrillation (VF), or cardiac arrest
• •8. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug
• •9. Malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug
• •10. Active severe or uncontrolled chronic infection, including but not limited to, the requirement for intravenous antibiotics for longer than 2 weeks
• •11. History of HIV infection. Testing is not required in the absence of history.
• •12. Chronic hepatitis B (surface antigen-positive) or chronic active hepatitis C infection. Testing is not required in the absence of history.
• •13. Any serious medical condition or psychiatric illness that could, in the investigator's opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol
• •14. Known or suspected hypersensitivity to brigatinib or other TKI or their excipients
• •15. Life-threatening illness unrelated to cancer
• •16. Involvement in the planning and/or conduct of the study (applies to both Takeda staff and/or staff of sponsor and study site)
• •17. Patient who might be dependent on the sponsor, site or the investigator
• •18. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities \[according to national Medicinal Products Act (Arzneimittelgesetz, AMG)\]
• •19. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[according to national AMG\]
• •20. Legal incapacity or limited legal capacity
• •21. Females who are pregnant or breastfeeding
• •22. Patients who have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization.
• •NOTE: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7 days prior to randomization.
• •23. Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption