A Study to Evaluate the Efficacy of Brigatinib (AP26113) in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.

Detailed Description
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The drug being tested in this study is called brigatinib (AP26113). Brigatinib was tested to treat people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or were intolerant to crizotinib. This study looked at the efficacy of brigatinib. The study enrolled 222 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups: Brigatinib 90 mg Brigatinib 90 mg -180 mg All participants were asked to take a tablet, orally once daily until disease progression or intolerable toxicity. Participants in Brigatinib 90 mg - 180 mg received 180 mg with a 7-day lead-in at 90 mg. This multi-center trial was conducted worldwide. The overall time to participate in this study is up to 3 years. Participants will make multiple visits to the clinic, and 3 months after the End-of-Treatment visit. Follow-up is intended to continue for 2 years after the last participants was enrolled into the study.

Official Title
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A Randomized Phase 2 Study of AP26113 in Patients With ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Brigatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically or cytologically confirmed locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is anaplastic lymphoma kinase (ALK+). Must meet one of the following two criteria: Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or Have documented ALK positivity by a different test and tissue available for the Vysis® FISH test. Tissue should be derived preferably from a biopsy taken after progression with crizotinib. If such a sample is not available, testing may be performed with archived tumor tissue. Had progressive disease while on crizotinib, as assessed by the investigator or treating physician. Have at least 1 measurable lesion per RECIST v1.1. Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy. Brain lesions may not be used as target lesions if they were: 1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical resection. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade ≤2. Are a male or female participants ≥18 years old. Have a life expectancy ≥3 months. Have adequate organ and hematologic function, as determined by: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN; ≤5 x ULN is acceptable if liver metastases are present) Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for participants with Gilbert syndrome) Serum creatinine ≤1.5 x ULN Serum lipase/amylase ≤1.5 x ULN Absolute neutrophil count (ANC) ≥1500/µL Platelets ≥75000/µL Hemoglobin ≥10 g/dL Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females. For female participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment. Female and male participants who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation. Must provide a signed and dated informed consent indicating that the participants has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating. Have the willingness and ability to comply with scheduled visits and study procedures. Exclusion Criteria: Received any prior ALK-targeted TKI other than crizotinib. Received crizotinib within 3 days of the first dose of brigatinib (Day 1, Cycle 1). Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except SRS or stereotactic body radiosurgery. Received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib (Day 1, Cycle 1). Have been diagnosed with another primary malignancy within the past 3 years (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, which are allowed within 3 years). Have symptomatic CNS metastases that are neurologically unstable or require an increasing dose of corticosteroids. Have current spinal cord compression. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: Myocardial infarction (MI) within 6 months prior to the first dose of brigatinib Unstable angina within 6 months prior to first dose Congestive heart failure (CHF) within 6 months prior to first dose History of clinically significant (as determined by the treating physician) atrial arrhythmia Any history of ventricular arrhythmia Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose Have a history or the presence of pulmonary interstitial disease or drug-related pneumonitis. Have an ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection. Have a known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history. Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose of brigatinib. Have a known or suspected hypersensitivity to brigatinib or its excipients. Have malabsorption syndrome or other GI illness that could affect oral absorption of the study drug. Have any condition or illness that, in the opinion of the investigator, would compromise participants safety or interfere with evaluation of the drug study. Be pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brigatinib 90 mg<br>Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days). | Drug: Brigatinib<br>* Brigatinib tablets<br>* Other names: ALUNBRIG™;|
| Experimental: Brigatinib 90 mg - 180 mg<br>Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days). | Drug: Brigatinib<br>* Brigatinib tablets<br>* Other names: ALUNBRIG™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) as Assessed by Investigator | ORR assessed by the investigator, was defined as percentage of the participants with confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) v1.1 (confirmed ≥4 weeks after initial response), after initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 97.5% confidence interval was calculated. The treatment regimen was considered to have achieved the primary objective when lower bound of the 97.5% confidence interval for ORR assessed by investigator is greater than 20%. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC) | ORR assessed by the IRC, was defined as the percentage of the participants with CR or PR according to RECIST v1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in theSLD of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months) | 
| Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Measurable Active Brain Metastases | Confirmed intracranial CNS ORR was defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months | 
| Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Only Non-measurable Active Brain Metastases | Confirmed intracranial CNS ORR is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months | 
| Intracranial CNS Progression Free Survival (PFS) in Participants With Active Brain Metastases | Intracranial CNS PFS as evaluated by IRC is defined as the time interval from the date of the first dose of the study drug until the first date at which intracranial CNS disease progression, an increase of 20% or more in the sum of diameters of intracranial CNS target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions in the intracranial CNS, was objectively documented by a scan, or death due to any cause, whichever occurred first. The analysis was based on the Kaplan-Meier (KM) Estimates. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months | 
| Time to Response | Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters. | Up to approximately 69 months | 
| Duration of Response | Duration of response was defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death. Patients without progressive disease or death were censored at the last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. The analysis was based on the Kaplan-Meier (KM) Estimates. | Up to approximately 69 months | 
| Time on Treatment | Time on treatment was defined as the time from the first to the last dose of study drug. For participants who have not discontinued, time on treatment was censored as of the last dose of the study drug. | Up to approximately 69 months | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of randomized participants who were confirmed to have achieved CR or PR or have a best overall response as stable disease (SD) for 6 weeks or more after initiation of the study drug. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 20% increase in the sum of diameters of target lesions. | Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months) | 
| Progression Free Survival (PFS) | PFS was defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). The analysis was based on the Kaplan-Meier (KM) Estimates. | Up to approximately 69 months | 
| Overall Survival (OS) | OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Intracranial OS was calculated by Kaplan-Meier estimation. | Up to approximately 69 months | 
| Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE) | An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug. | From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months) | 
| Pre-dose Brigatinib Plasma Concentration |  | Day 1 Cycles 2, 3, 4 and 5 (each Cycle of 28-days) pre-dose | 
| Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores | Patient-reported symptoms global health status/quality of life (QoL) scores were based on questions 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30). The first 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and last 2 questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Six single-item scales also are included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores for multi-item scales and single-item measures was linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher (better) level of functioning. | Baseline and at each 28-day cycle up to end of the study (up to approximately 69 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy