Table 1 Inclusion and exclusion criteria
INCLUSION CRITERIA | • Fully informed written consent and any locally-required authorization (EU Data Privacy Directive) given by the patient • Male or female ≥18 years of age • Histologically confirmed locally advanced (stage III) and not suitable for curative treatment, i.e. R0 operation or definitive chemo−/radiation, or metastatic (stage IV) ALK+ NSCLC NOTE: Documentation of ALK rearrangement confirmed at baseline by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridization (FISH)]. Treatment may be started based on a local ALK+ test result, but subsequent central molecular profiling of the baseline biopsy, incl. determination of ALK variant and TP53 status, should be made possible for all patients. • No prior therapy for metastatic ALK+ NSCLC including ALK inhibitors (up to two cycles of chemotherapy as well as cerebral irradiation before inclusion in the study are acceptable) • At least 1 measurable (i.e., target) lesion according to RECIST 1.1 • ECOG performance status ≤2 • Adequate organ function, as determined by: - Total bilirubin ≤1.5x the upper limit of the normal range (ULN) (< 3x the ULN in case of Gilbert’s disease) - Estimated glomerular filtration rate ≥ 30 mL/minute/1.73 m2 (calculated by MDRD or any other validated formula) - Alanine aminotransferase/aspartate aminotransferase ≤2.5x ULN NOTE: ≤5x ULN is acceptable in case of liver metastases - Serum lipase ≤1.5x ULN - Platelet count ≥75 × 109/L - Hemoglobin ≥9 g/dL - Absolute neutrophil count ≥1.5 × 109/L • Willingness and ability to comply with scheduled visits and study procedures • Willingness to participate in accompanying research program • Collection of current biopsies during screening must be feasible NOTE: For each patient a FFPE-tumor tissue block must be available for biomarker evaluation. Excisional, incisional or core needle biopsies are appropriate, while fine needle aspirations are insufficient. • Women of childbearing potential must have a negative pregnancy test result within 7 days before randomization. Women must not be breastfeeding. • Females who are postmenopausal for at least 1 year before the screening visit OR are surgically sterile OR, if they are of childbearing potential, agree to practice two effective methods of contraception simultaneously, from the time of signing the informed consent until 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Males, even if surgically sterilized (i.e., status post vasectomy), who agree to practice effective barrier contraception during the entire study treatment period and until 4 months after the last dose of study drug, OR agree to completely abstain from heterosexual intercourse. |
EXCLUSION CRITERIA | • History or presence of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis at baseline • Uncontrolled hypertension (hypertension must be adequately treated for control of blood pressure upon study entry) • 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 stereotactic radiosurgery or stereotactic body radiation therapy) within 14 days of randomization • Treatment with antineoplastic monoclonal antibodies within 30 days of randomization • Major surgery within 30 days of randomization. Minor surgical procedures are allowed, such as catheter placement or minimally invasive biopsies. • Current spinal cord compression (symptomatic or asymptomatic). Patients with leptomeningeal disease without spinal cord compression may participate. • Significant or uncontrolled cardiovascular disease, specifically including, but not restricted to the following: - If an acute coronary syndrome has ensued in the past six months, successful reperfusion has to be documented and the patient must be asymptomatic - New York Heart Association Class III or IV heart failure within six months prior to randomization - Any history of clinically significant ventricular arrhythmia • Cerebrovascular accident or transient ischemic attack within six months prior to first dose of study drug • Malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug • Active severe or uncontrolled chronic infection, including but not limited to, the requirement for intravenous antibiotics for longer than two weeks • History of HIV infection. Testing is not required in the absence of history. • Chronic hepatitis B (surface antigen-positive) or chronic active hepatitis C infection. Testing is not required in the absence of history. • 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 • Known or suspected hypersensitivity to brigatinib or other TKI or their excipients • Life-threatening illness unrelated to cancer • Involvement in the planning and/or conduct of the study (applies to both Takeda staff and/or staff of sponsor and study site) • Patient who might be dependent on the sponsor, site or investigator • Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG] • 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 [§ 40 Abs. 1 S. 3 Nr. 3a AMG] • Legal incapacity or limited legal capacity • Females who are pregnant or breastfeeding • 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 before randomization. NOTE: If a patient has worsening neurological symptoms due to CNS metastasis, they must have completed local therapy and be neurologically stable (without requiring an increasing dose of corticosteroids or anticonvulsants) seven days before randomization. • Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption |