NCT04318938.

Study name	Advancing brigatinib properties in ALK+ NSCLC patients by deep phenotyping
Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics 1L: Any approved second‐generation ALK TKI (investigator's choice) 2L: Any ALK TKI including brigatinib (investigator's choice) Median age (range): Female %: Ethnicity Asian %: ECOG 0 to 1 %: Never smoked %: Stage of disease IV at entry %: Adenocarcinoma %: Brain metastases at entry %: Previous chemotherapy %: Previous targeted therapy %: 1L: Brigatinib 90 mg orally, daily for 7/7 then 180 mg orally, daily, continuously 2L: Any ALK TKI (investigator's choice) Median age (range): Female %: Ethnicity Asian %: ECOG 0 to 1 %: Never smoked %: Stage of disease IV at entry %: Adenocarcinoma %: Brain metastases at entry %: Previous chemotherapy %: Previous targeted therapy %: Inclusion criteria Fully informed written consent and any locally required authorisation (EU Data Privacy Directive) given by the patient. Male or female ≥ 18 years of age. NOTE: There are no data that indicate special gender distribution, therefore patients will be enrolled in the study gender‐independently. 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 by a positive result of any ALK assay approved in Germany (i.e. positivity for at least 1 of the 3: immunohistochemistry (IHC), next‐generation sequencing, fluorescence in situ hybridisation (FISH)) must be available at baseline. Treatment can already be started based on a local ALK+ test result, but subsequent central testing of the baseline biopsy for molecular profiling, including determination of ALK variant and TP53 status, should be made possible for all patients. No prior therapy for metastatic ALK+ NSCLC including therapy with ALK inhibitors. However, 1 or 2 cycles of chemotherapy as well as cerebral irradiation before inclusion in the study will be allowed. At least 1 measurable (i.e. target) lesion per RECIST v1.1 ECOG PS ≤ 2. Have adequate organ function, as determined by the following: Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) (< 3 x the ULN if Gilbert's disease is present) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m² (calculated by Modification of Diet in Renal Disease (MDRD) or any other validated formula, see Appendix 13.4) Alanine aminotransferase/aspartate aminotransferase ≤ 2.5 x ULN NOTE: ≤ 5 x ULN is acceptable if liver metastases are present. Serum lipase ≤ 1.5 x ULN Platelet count ≥ 75 x 10^9/L Haemoglobin ≥ 9 g/dL Absolute neutrophil count ≥ 1.5 x 10^9/L Willingness and ability to comply with scheduled visit and study procedures. Patient willing to participate in accompanying research programme. Collection of current biopsy during screening must be feasible. NOTE: For each patient a formalin‐fixed, paraffin‐embedded (FFPE) tumour tissue block must be available for biomarker evaluation. Excisional, incisional, or core needle biopsies are appropriate, whilst fine‐needle aspirations are insufficient. Women of childbearing potential must have a negative pregnancy test within 7 days prior to randomisation. Women must not be breastfeeding. Female patients 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 highly effective non‐hormonal contraception from the time of signing the informed consent through at least 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilised (i.e. status postvasectomy), who: agree to practice effective barrier contraception during the entire study treatment period and through at least 4 months after the last dose of study drug, OR agree to completely abstain from heterosexual intercourse Exclusion criteria History or presence at baseline of pulmonary interstitial disease, drug‐related pneumonitis, or radiation pneumonitis. Uncontrolled hypertension, defined as hypertension treated* with antihypertensive 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 antihypertensive adjustment. *NOTE: In case of treatment, at least 3 antihypertensive drugs should have been used with the intention to control hypertensive disease. 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 body radiation therapy) within 14 days of randomisation. Treatment with antineoplastic monoclonal antibodies within 30 days of randomisation. Major surgery within 30 days of randomisation. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed. Current spinal cord compression (symptomatic or asymptomatic) as detected by radiographic imaging. Patients with leptomeningeal disease without cord compression are allowed. 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 to 100 m); comfortable only at rest) within 6 months prior to randomisation. Any history of clinically significant ventricular arrhythmia, defined as ventricular tachycardia (VT), ventricular fibrillation (VF), or cardiac arrest. Cerebrovascular accident or transient ischaemic attack within 6 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 2 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 the investigator. Patient who has been incarcerated or involuntarily institutionalised by court order or by the authorities (according to national Medicinal Products Act (Arzneimittelgesetz, 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 (according to national 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 prior to randomisation. 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 randomisation. Rare hereditary galactose intolerance, total lactase deficiency, or glucose‐galactose malabsorption
Interventions	Intervention characteristics 1L: Any approved second‐generation ALK TKI (investigator's choice) 2L: Any ALK TKI including brigatinib (investigator's choice) Type: TKI 1L: Brigatinib 90 mg orally, daily for 7/7 then 180 mg orally, daily, continuously 2L: Any ALK TKI (investigator's choice) Type: TKI
Outcomes	Progression‐free survival (PFS) of first‐line treatment according to RECIST v1.1 [ Time Frame: 68 months ] PFS of second‐line treatment according to RECIST v1.1 [ Time Frame: 68 months TNT first line (TNT1, i.e. time‐to‐next treatment for the first line) [ Time Frame: 68 months ] TNT second line (TNT2, i.e. time‐to‐next treatment for the second line [ Time Frame: 68 months ] TNT1/2 (time‐to‐next treatment for the first and second line together) [ Time Frame: 68 months ] Overall survival (OS) [ Time Frame: 68 months] Intracranial overall response rate (iORR) [ Time Frame: 68 months ] Intracranial duration of response (iDOR) according to RECIST v1.1 [ Time Frame: 68 months ] Time to intracranial progression (TTiP) [ Time Frame: 68 months ] Safety (rate of adverse events) [ Time Frame: 68 months ] Quality of life assessed by 12‐item Short Form Health Survey (SF‐12) [ Time Frame: 68 months ] Quality of life assessed by EORTC QLQ‐BN20 [ Time Frame: 68 months ]
Starting date	March 2020
Contact information	Michael Thomas, Prof: Michael.Thomas@med.uni‐heidelberg.de Regina Eickhoff, Dr; eickhoff.regina@ikf‐khnw.de
Notes	clinicaltrials.gov/ct2/show/NCT04318938