Advancing Brigatinib Properties in ALK+ NSCLC Patients by Deep Phenotyping
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|ClinicalTrials.gov Identifier: NCT04318938|
Recruitment Status : Recruiting
First Posted : March 24, 2020
Last Update Posted : November 14, 2022
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|Condition or disease||Intervention/treatment||Phase|
|NSCLC||Drug: Brigatinib Drug: Tyrosine kinase inhibitor||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||116 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Advancing Brigatinib Properties in Anaplastic Lymphoma Kinase Positive Non-small Cell Lung Cancer (ALK+ NSCLC) Patients|
|Actual Study Start Date :||March 30, 2020|
|Estimated Primary Completion Date :||December 31, 2025|
|Estimated Study Completion Date :||December 31, 2025|
Active Comparator: Standard Arm with any available ALK TKI
Drug: Tyrosine kinase inhibitor
Treatment with any TKI
Other Name: Study treatment
Experimental: Experimental Arm with Brigatinib
Treatment with Brigatinib
Other Name: Study treatment
- Progression-free survival (PFS) of 1st-line treatment according to RECIST v1.1 [ Time Frame: 68 months ]Time from the first dosing date of any study medication to the date of the first objectively documented tumor progression or death due to any cause
- PFS of 2nd-line treatment according to RECIST v1.1 [ Time Frame: 68 months ]Time from the first dosing date of any 2nd-line TKI to the date of the objectively documented tumor progression or death due to any cause
- TNT 1st line (TNT1, i.e. time-to-next treatment for the 1st line) [ Time Frame: 68 months ]Time from begin of 1st-line treatment until begin of 2nd-line treatment
- TNT 2nd line (TNT2, i.e. time-to-next treatment for the 2nd line [ Time Frame: 68 months ]Time from begin of 2nd line until begin of 3rd-line treatment
- TNT1/2 (time-to-next treatment for the 1st and 2nd line together) [ Time Frame: 68 months ]Time from begin of 1st-line treatment until begin of 3rd-line treatment
- Overall survival (OS) [ Time Frame: 68 months ]Time from treatment start in the 1st line to the date of death (due to any cause)
- Intracranial ORR (iORR) [ Time Frame: 68 months ]Percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented intracranial tumor progression per RECIST criteria or the date of subsequent therapy or death, whichever occurs first
- Intracranial DOR (iDOR) according to RECIST v1.1 [ Time Frame: 68 months ]Time from documentation of CR or PR according to RECIST v1.1 (whichever is first recorded) until the first date that the intracranial progressive disease (PD) is objectively documented or until death (whichever occurs first
- Time to intracranial progression (TTiP) [ Time Frame: 68 months ]Time from start of 1st-line treatment until the occurrence of a new central nervous system (CNS) lesion or progression of pre-existing CNS lesions
- Safety (rate of adverse events) [ Time Frame: 68 months ]Type, incidence and severity of adverse events (AEs) and serious adverse events (SAEs)graded according to NCI CTCAE v5.0
- Quality of life (QoL) assessed by SF-12-questionnaire [ Time Frame: 68 months ]Patient reported outcome assessed by the validated SF-12-questionnaire
- Quality of life (QoL) assessed by EORTC-quality of life questionnaire (QLQ)-BN20-questionnaire [ Time Frame: 68 months ]Patient reported outcome assessed by the validated EORTC-QLQ-BN20-questionnaire
- ALK variant analysis in tumor tissue [ Time Frame: 68 months ]Typing of ALK fusion variants in tumor samples
- ALK variant analysis in blood samples [ Time Frame: 68 months ]Typing of ALK fusion variants in blood samples
- TP53 mutation status in tumor tissue [ Time Frame: 68 months ]Assessment of TP53 mutation status in tumor samples
- TP53 mutation status in blood samples [ Time Frame: 68 months ]Assessment of TP53 mutation status in blood samples
- Detection of "acquired resistance" mutations in tumor tissue [ Time Frame: 68 months ]Detection of "acquired resistance" mutations via standardized next-generation sequencing (NGS)-based multiplex analysis in tumor samples
- Detection of "acquired resistance" mutations in blood samples [ Time Frame: 68 months ]Detection of "acquired resistance" mutations via standardized next-generation sequencing (NGS)-based multiplex analysis in blood samples
- ALK variant analysis in cerebrospinal fluid [ Time Frame: 68 months ]Typing of ALK fusion variants in cerebrospinal fluid in "brain-only" progression.
- TP53 mutation status in cerebrospinal fluid [ Time Frame: 68 months ]Assessment of TP53 mutation status in cerebrospinal fluid in "brain-only" progression.
- Detection of "acquired resistance" mutations in cerebrospinal fluid [ Time Frame: 68 months ]Detection of "acquired resistance" mutations via standardized circulating tumor DNA (ctDNA) next-generation sequencing (NGS)-based multiplex analysis in cerebrospinal fluid
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Fully informed written consent and any locally-required authorization (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 one of the three: immunohistochemistry (IHC), NGS, 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, incl. 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
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Have adequate organ function, as determined by:
- Total bilirubin ≤1.5x the upper limit of the normal range (ULN) (< 3x the ULN if Gilbert's disease is present)
- Estimated glomerular filtration rate ≥30 mL/minute/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 ≤2.5x ULN NOTE: ≤5x ULN is acceptable if liver metastases are present.
- Serum lipase ≤1.5x ULN
- Platelet count ≥75x 109/L
- Hemoglobin ≥9 g/dL
- Absolute neutrophil count ≥1.5x 109/L
- Willingness and ability to comply with scheduled visit and study procedures
- Patient willing to participate in accompanying research program
- Collection of current biopsy during screening must be feasible NOTE: For each patient a formalin-fixed, paraffin-embedded (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 (WOCBP) must have a negative pregnancy test within 7 days prior to randomization. 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 sterilized (i.e., status post-vasectomy), 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.
- History or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
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 note: In case of treatment, at least 3 anti-hypertensive 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 randomization
- Treatment with antineoplastic monoclonal antibodies within 30 days of randomization
- Major surgery within 30 days of randomization. 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 (20-100 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
- Cerebrovascular accident or transient ischemic 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 institutionalized 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 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.
- Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04318938
|Contact: Michael Thomas, Prof.||+49 6221 396 ext 1301||Michael.Thomas@med.uni-heidelberg.de|
|Contact: Regina Eickhoff, Dr.||+49 69 7601 ext email@example.com|
|Study Director:||Salah-Eddin Al-Batran, Prof.||Institut für Klinische Krebsforschung IKF GmbH|
|Responsible Party:||Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest|
|Other Study ID Numbers:||
|First Posted:||March 24, 2020 Key Record Dates|
|Last Update Posted:||November 14, 2022|
|Last Verified:||November 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Plan Description:||No IPD will be shared|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Tyrosine Protein Kinase Inhibitors
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action