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Trial record 1 of 1 for:    NCT02094573
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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

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ClinicalTrials.gov Identifier: NCT02094573
Recruitment Status : Active, not recruiting
First Posted : March 24, 2014
Results First Posted : June 21, 2017
Last Update Posted : October 3, 2017
Sponsor:
Information provided by (Responsible Party):
Ariad Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Intervention Drug: Brigatinib
Enrollment 222
Recruitment Details Participants took part in the study at 94 investigative sites in the United States, Canada, Europe, Australia and Asia from 04 Jun 2014 up to clinical cut-off date 29 Feb 2016. Study is ongoing.
Pre-assignment Details Participants with ALK-positive, locally advanced or metastatic NSCLC who were treated with crizotinib were enrolled to receive brigatinib 90 mg, once daily or brigatinib 90-180 mg, once daily.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity. 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.
Period Title: Overall Study
Started 112 110
Treated 109 110
Completed 0 0
Not Completed 112 110
Reason Not Completed
Documented Progressive Disease             29             16
Clinical Progressive Disease             4             3
Adverse Event             3             9
Death             7             1
Non-compliance with study drug             0             1
Withdrawal by Subject             2             4
Randomized but not treated             3             0
Ongoing             64             76
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg Total
Hide Arm/Group Description Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity. 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. Total of all reporting groups
Overall Number of Baseline Participants 112 110 222
Hide Baseline Analysis Population Description
Intention to Treat (ITT) Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhere to the assigned dose.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 112 participants 110 participants 222 participants
51.5  (13.01) 55.5  (12.96) 53.4  (13.11)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 112 participants 110 participants 222 participants
18-49 years 50 33 83
50-64 years 40 47 87
65-74 years 20 23 43
≥75 years 2 7 9
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants 110 participants 222 participants
Female
62
  55.4%
64
  58.2%
126
  56.8%
Male
50
  44.6%
46
  41.8%
96
  43.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 112 participants 110 participants 222 participants
White 72 76 148
Black or African American 1 2 3
Asian 39 30 69
Unknown 0 2 2
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 112 participants 110 participants 222 participants
Hispanic or Latino 5 8 13
Not Hispanic or Latino 107 102 209
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 112 participants 110 participants 222 participants
Australia 3 6 9
Austria 3 6 9
Belgium 3 2 5
Canada 2 1 3
Denmark 2 6 8
France 4 2 6
Germany 7 7 14
Hong Kong 6 0 6
Italy 15 14 29
Netherlands 6 6 12
Norway 1 1 2
Singapore 4 3 7
Spain 5 7 12
Sweden 2 2 4
Switzerland 0 1 1
United Kingdom 2 1 3
United States 21 25 46
Korea, Republic Of 26 20 46
1.Primary Outcome
Title Confirmed Objective Response Rate (ORR) as Assessed by Investigator
Hide Description ORR assessed by the investigator, is defined as proportion 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%.
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to Treat (ITT) Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Measure Type: Number
Number (97.5% Confidence Interval)
Unit of Measure: percentage of participants
44.6
(34.0 to 55.6)
53.6
(42.6 to 64.5)
2.Secondary Outcome
Title Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)
Hide Description ORR assessed by the IRC, is defined as the proportion of the participants with confirmed Clinical response (CR) or partial response (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 the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated.
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
48.2
(38.7 to 57.9)
52.7
(43.0 to 62.3)
3.Secondary Outcome
Title Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Measurable Active Brain Metastases
Hide Description Confirmed intracranial CNS ORR is defined as the proportion 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 sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date:29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with measurable active brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 19 15
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
42.1
(20.3 to 66.5)
73.3
(44.9 to 92.2)
4.Secondary Outcome
Title Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Only Non-measurable Active Brain Metastases
Hide Description Confirmed intracranial CNS ORR is defined as the proportion 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 sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date:29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with only non-measurable active brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 32 36
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
9.4
(2.0 to 25.0)
19.4
(8.2 to 36.0)
5.Secondary Outcome
Title Intracranial CNS Progression Free Survival (PFS) in Participants With Active Brain Metastases
Hide Description 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.
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with active brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 51 51
Median (95% Confidence Interval)
Unit of Measure: months
15.6
(7.3 to 15.7)
11.1 [1] 
(7.4 to NA)
[1]
Upper limit of PFS was not reached.
6.Secondary Outcome
Title Time to Response
Hide Description Time to response is 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 sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.
Time Frame Up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 50 59
Median (Full Range)
Unit of Measure: months
1.8
(1.7 to 9.1)
1.9
(1.0 to 11.0)
7.Secondary Outcome
Title Duration of Response
Hide Description Duration of response is 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 sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.
Time Frame Up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 50 59
Median (95% Confidence Interval)
Unit of Measure: months
13.8
(5.6 to 13.8)
11.1
(9.2 to 13.8)
8.Secondary Outcome
Title Time on Treatment
Hide Description Time on treatment is 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.
Time Frame Up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least one dose of study drug.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 109 110
Mean (Standard Deviation)
Unit of Measure: days
231.6  (129.19) 251.9  (137.93)
9.Secondary Outcome
Title Disease Control Rate
Hide Description Disease control rate (DCR) is defined as the proportion 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 sum of the longest diameters (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).
Time Frame Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered cycle) through 15 cycles and every 3 cycles thereafter until disease progression or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
82.1
(73.8 to 88.7)
86.4
(78.5 to 92.2)
10.Secondary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS is 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).
Time Frame Up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Median (95% Confidence Interval)
Unit of Measure: months
9.2
(7.4 to 15.6)
12.9 [1] 
(11.1 to NA)
[1]
Upper limit of PFS was not reached.
11.Secondary Outcome
Title Overall Survival (OS)
Hide Description 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.
Time Frame Up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Median (95% Confidence Interval)
Unit of Measure: months
Overall Survival
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
1 Year Overall Survival
70.6
(59.8 to 79.1)
79.5
(66.9 to 87.7)
[1]
The median OS and 95% CI were not reached due to relatively lower number of deaths occurred by the time of clinical cut-off date.
12.Secondary Outcome
Title Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
Hide Description An Adverse Event (AE) is 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame From first dose of study drug up to 30 days following the last dose of study drug (up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least one dose of study drug.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 109 110
Measure Type: Number
Unit of Measure: participants
106 110
13.Secondary Outcome
Title Pre-dose Brigatinib Plasma Concentration
Hide Description [Not Specified]
Time Frame Day 1 Cycle 1 pre-dose; Cycle 2 pre-dose and at multiple time points (up to 6-8 hours) post dose; Cycles 3, 4 and 5 pre-dose and at 1-8 hours post dose
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Mean (Standard Deviation)
Unit of Measure: ng/ml
Cycle 2 (n=101, 97) 295.2  (252.0) 520.0  (321.9)
Cycle 3 (n=91, 92) 263.9  (238.9) 537.0  (360.3)
Cycle 4 (n=80, 87) 236.1  (188.0) 564.7  (415.0)
Cycle 5 (n=80, 79) 256.4  (282.3) 579.7  (396.7)
14.Secondary Outcome
Title Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores
Hide Description 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 will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
Time Frame Up to 30 days after the last dose of study drug or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Here, n represents number of participants who were evaluable at specific time point.
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description:
Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity.
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.
Overall Number of Participants Analyzed 112 110
Mean (Standard Deviation)
Unit of Measure: unit on a scale
Baseline (n=108, 108) 52.39  (27.42) 58.49  (23.40)
Cycle 2 (n=101, 97) 64.19  (20.73) 65.72  (19.54)
Cycle 3 (n=91, 91) 65.57  (24.06) 68.50  (20.52)
Cycle 4 (n=84, 89) 69.44  (20.59) 66.95  (20.89)
Cycle 5 (n=82, 84) 70.12  (20.28) 72.12  (17.57)
Cycle 6 (n=78, 81) 69.76  (20.02) 71.50  (18.63)
Cycle 7 (n=75, 76) 67.56  (20.53) 71.05  (19.88)
Cycle 8 (n=61, 70) 66.12  (22.46) 70.95  (19.95)
Cycle 9 (n=53, 57) 67.77  (22.82) 70.32  (19.48)
Cycle 10 (n=42, 47) 69.64  (22.07) 68.97  (22.43)
Cycle 11 (n=29, 39) 69.54  (21.97) 69.87  (22.43)
Cycle 12 (n=26, 33) 60.90  (24.47) 73.48  (23.15)
Cycle 13 (n=20, 27) 65.00  (20.52) 74.07  (21.72)
Cycle 14 (n=15, 22) 62.22  (24.57) 73.11  (22.56)
Cycle 15 (n=12, 17) 64.58  (25.41) 74.02  (24.81)
Cycle 16 (n=9,12) 64.81  (27.25) 74.31  (18.62)
Cycle 17 (n=4, 7) 75.00  (11.79) 75.00  (24.06)
Cycle 18 (n=1, 5) 100.00 [1]   (NA) 78.33  (21.73)
Cycle 19 (n=0, 2) NA [2]   (NA) 66.67  (47.14)
Cycle 20 (n=0,2) NA [2]   (NA) 70.83  (41.25)
Cycle 21 (n=0,2) NA [2]   (NA) 62.50  (5.89)
End of Treatment (n=30, 12) 37.78  (25.87) 48.61  (13.69)
Follow-Up 30 Days After Last Dose (n=11, 10) 43.94  (32.93) 60.00  (15.61)
[1]
Only 1 participant was analyzed at this time point.
[2]
No participant was analyzed for this time point.
Time Frame From first dose of study drug up to 30 days following the last dose of study drug or up to data cut-off date: 29 Feb 2016 (approximately up to 20 months)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Hide Arm/Group Description Brigatinib 90 mg, tablets, orally, once daily in each cycle of 28 days until disease progression or intolerable toxicity. 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.
All-Cause Mortality
Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   41/109 (37.61%)   44/110 (40.00%) 
Ear and labyrinth disorders     
Vertigo Positional  1  2/109 (1.83%)  0/110 (0.00%) 
Eye disorders     
Macular Oedema  1  0/109 (0.00%)  1/110 (0.91%) 
Gastrointestinal disorders     
Abdominal Pain  1  1/109 (0.92%)  0/110 (0.00%) 
Diarrhoea  1  1/109 (0.92%)  0/110 (0.00%) 
Food Poisoning  1  0/109 (0.00%)  1/110 (0.91%) 
Gastrointestinal Haemorrhage  1  1/109 (0.92%)  0/110 (0.00%) 
Small Intestinal Obstruction  1  1/109 (0.92%)  0/110 (0.00%) 
General disorders     
Device Occlusion  1  1/109 (0.92%)  1/110 (0.91%) 
General Physical Health Deterioration  1  1/109 (0.92%)  1/110 (0.91%) 
Asthenia  1  1/109 (0.92%)  0/110 (0.00%) 
Infusion Site Thrombosis  1  0/109 (0.00%)  1/110 (0.91%) 
Sudden Death  1 [1]  0/109 (0.00%)  1/110 (0.91%) 
Hepatobiliary disorders     
Cholangitis Acute  1  1/109 (0.92%)  0/110 (0.00%) 
Jaundice Cholestatic  1  0/109 (0.00%)  1/110 (0.91%) 
Infections and infestations     
Pneumonia  1 [2]  3/109 (2.75%)  8/110 (7.27%) 
Appendicitis  1  1/109 (0.92%)  1/110 (0.91%) 
Bronchitis  1  1/109 (0.92%)  1/110 (0.91%) 
Atypical Pneumonia  1  1/109 (0.92%)  0/110 (0.00%) 
Cellulitis  1  0/109 (0.00%)  1/110 (0.91%) 
Meningitis Bacterial  1 [3]  1/109 (0.92%)  0/110 (0.00%) 
Tuberculous Pleurisy  1  0/109 (0.00%)  1/110 (0.91%) 
Urosepsis  1 [3]  1/109 (0.92%)  0/110 (0.00%) 
Injury, poisoning and procedural complications     
Post Procedural Haemorrhage  1  0/109 (0.00%)  2/110 (1.82%) 
Head Injury  1  0/109 (0.00%)  1/110 (0.91%) 
Laceration  1  1/109 (0.92%)  0/110 (0.00%) 
Radiation Necrosis  1  0/109 (0.00%)  1/110 (0.91%) 
Radiation Pneumonitis  1  0/109 (0.00%)  1/110 (0.91%) 
Investigations     
Neutrophil Count Decreased  1  0/109 (0.00%)  1/110 (0.91%) 
Metabolism and nutrition disorders     
Dehydration  1  1/109 (0.92%)  0/110 (0.00%) 
Hyponatraemia  1  0/109 (0.00%)  1/110 (0.91%) 
Musculoskeletal and connective tissue disorders     
Back Pain  1  1/109 (0.92%)  1/110 (0.91%) 
Arthralgia  1  1/109 (0.92%)  0/110 (0.00%) 
Neck Pain  1  1/109 (0.92%)  0/110 (0.00%) 
Pathological Fracture  1  1/109 (0.92%)  0/110 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasm Progression  1 [4]  13/109 (11.93%)  5/110 (4.55%) 
Malignant Pleural Effusion  1 [3]  3/109 (2.75%)  3/110 (2.73%) 
Metastases To Central Nervous System  1  0/109 (0.00%)  1/110 (0.91%) 
Metastases To Meninges  1 [3]  1/109 (0.92%)  0/110 (0.00%) 
Nervous system disorders     
Epilepsy  1  3/109 (2.75%)  1/110 (0.91%) 
Cerebrovascular Accident  1  1/109 (0.92%)  0/110 (0.00%) 
Dysaesthesia  1  0/109 (0.00%)  1/110 (0.91%) 
Generalised Tonic-Clonic Seizure  1  1/109 (0.92%)  0/110 (0.00%) 
Headache  1  0/109 (0.00%)  1/110 (0.91%) 
Nervous System Disorder  1  0/109 (0.00%)  1/110 (0.91%) 
Seizure  1  0/109 (0.00%)  1/110 (0.91%) 
Simple Partial Seizures  1  0/109 (0.00%)  1/110 (0.91%) 
Spinal Cord Compression  1  1/109 (0.92%)  0/110 (0.00%) 
Syncope  1  1/109 (0.92%)  0/110 (0.00%) 
Transient Ischaemic Attack  1  1/109 (0.92%)  0/110 (0.00%) 
Psychiatric disorders     
Confusional State  1  0/109 (0.00%)  1/110 (0.91%) 
Renal and urinary disorders     
Hydronephrosis  1  1/109 (0.92%)  0/110 (0.00%) 
Renal Impairment  1  1/109 (0.92%)  0/110 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pneumonitis  1  2/109 (1.83%)  8/110 (7.27%) 
Dyspnoea  1 [5]  2/109 (1.83%)  2/110 (1.82%) 
Pulmonary Embolism  1 [3]  2/109 (1.83%)  2/110 (1.82%) 
Dyspnoea Exertional  1  1/109 (0.92%)  0/110 (0.00%) 
Haemoptysis  1  0/109 (0.00%)  1/110 (0.91%) 
Pleural Effusion  1  1/109 (0.92%)  0/110 (0.00%) 
Respiratory Failure  1 [3]  1/109 (0.92%)  0/110 (0.00%) 
Skin and subcutaneous tissue disorders     
Angioedema  1  0/109 (0.00%)  1/110 (0.91%) 
Dermatitis Allergic  1  0/109 (0.00%)  1/110 (0.91%) 
Paraneoplastic Dermatomyositis  1  0/109 (0.00%)  1/110 (0.91%) 
Rash  1  1/109 (0.92%)  0/110 (0.00%) 
Vascular disorders     
Peripheral Artery Stenosis  1  0/109 (0.00%)  1/110 (0.91%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.0
[1]
1 treatment-emergent death occurred during treatment with brigatinib 90-180 mg and is possibly related.
[2]
1 treatment-emergent death occurred during treatment with brigatinib 90 mg and 1 treatment-emergent death occurred during treatment with brigatinib 90-180 mg and are not related.
[3]
1 treatment-emergent death occurred during treatment with brigatinib 90 mg and is not related.
[4]
9 treatment-emergent deaths occurred during treatment with brigatinib 90 mg and 4 treatment-emergent deaths occurred during treatment with brigatinib 90-180 mg and are not related.
[5]
1 treatment-emergent death occurred during treatment with brigatinib 90-180 mg and is not related.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Brigatinib 90 mg Brigatinib 90 mg - 180 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   103/109 (94.50%)   103/110 (93.64%) 
Ear and labyrinth disorders     
Vertigo  1  2/109 (1.83%)  10/110 (9.09%) 
Gastrointestinal disorders     
Nausea  1  36/109 (33.03%)  44/110 (40.00%) 
Diarrhoea  1  21/109 (19.27%)  42/110 (38.18%) 
Vomiting  1  26/109 (23.85%)  25/110 (22.73%) 
Constipation  1  21/109 (19.27%)  17/110 (15.45%) 
Abdominal Pain  1  17/109 (15.60%)  9/110 (8.18%) 
Dyspepsia  1  7/109 (6.42%)  6/110 (5.45%) 
Stomatitis  1  4/109 (3.67%)  8/110 (7.27%) 
Dry Mouth  1  2/109 (1.83%)  9/110 (8.18%) 
General disorders     
Fatigue  1  22/109 (20.18%)  30/110 (27.27%) 
Pyrexia  1  15/109 (13.76%)  7/110 (6.36%) 
Asthenia  1  9/109 (8.26%)  11/110 (10.00%) 
Oedema Peripheral  1  7/109 (6.42%)  8/110 (7.27%) 
Infections and infestations     
Nasopharyngitis  1  9/109 (8.26%)  9/110 (8.18%) 
Upper Respiratory Tract Infection  1  8/109 (7.34%)  6/110 (5.45%) 
Urinary Tract Infection  1  6/109 (5.50%)  7/110 (6.36%) 
Investigations     
Blood Creatine Phosphokinase Increased  1  12/109 (11.01%)  33/110 (30.00%) 
Amylase Increased  1  9/109 (8.26%)  16/110 (14.55%) 
Aspartate Aminotransferase Increased  1  9/109 (8.26%)  16/110 (14.55%) 
Lipase Increased  1  8/109 (7.34%)  13/110 (11.82%) 
Alanine Aminotransferase Increased  1  9/109 (8.26%)  10/110 (9.09%) 
Blood Lactate Dehydrogenase Increased  1  2/109 (1.83%)  9/110 (8.18%) 
Neutrophil Count Decreased  1  6/109 (5.50%)  5/110 (4.55%) 
Metabolism and nutrition disorders     
Decreased Appetite  1  24/109 (22.02%)  17/110 (15.45%) 
Musculoskeletal and connective tissue disorders     
Muscle Spasms  1  13/109 (11.93%)  19/110 (17.27%) 
Arthralgia  1  15/109 (13.76%)  15/110 (13.64%) 
Back Pain  1  10/109 (9.17%)  17/110 (15.45%) 
Pain in extremity  1  12/109 (11.01%)  4/110 (3.64%) 
Myalgia  1  6/109 (5.50%)  9/110 (8.18%) 
Musculoskeletal Pain  1  4/109 (3.67%)  9/110 (8.18%) 
Musculoskeletal Chest Pain  1  5/109 (4.59%)  7/110 (6.36%) 
Neck Pain  1  2/109 (1.83%)  7/110 (6.36%) 
Nervous system disorders     
Headache  1  30/109 (27.52%)  30/110 (27.27%) 
Dizziness  1  10/109 (9.17%)  9/110 (8.18%) 
Paraesthesia  1  10/109 (9.17%)  7/110 (6.36%) 
Peripheral Sensory Neuropathy  1  5/109 (4.59%)  7/110 (6.36%) 
Memory Impairment  1  2/109 (1.83%)  6/110 (5.45%) 
Psychiatric disorders     
Insomnia  1  12/109 (11.01%)  8/110 (7.27%) 
Renal and urinary disorders     
Haematuria  1  0/109 (0.00%)  6/110 (5.45%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  20/109 (18.35%)  37/110 (33.64%) 
Dyspnoea  1  21/109 (19.27%)  21/110 (19.09%) 
Oropharyngeal Pain  1  8/109 (7.34%)  7/110 (6.36%) 
Dysphonia  1  5/109 (4.59%)  6/110 (5.45%) 
Productive Cough  1  5/109 (4.59%)  4/110 (3.64%) 
Dyspnoea Exertional  1  6/109 (5.50%)  2/110 (1.82%) 
Haemoptysis  1  2/109 (1.83%)  6/110 (5.45%) 
Skin and subcutaneous tissue disorders     
Rash  1  8/109 (7.34%)  18/110 (16.36%) 
Pruritus  1  6/109 (5.50%)  7/110 (6.36%) 
Dermatitis Acneiform  1  6/109 (5.50%)  3/110 (2.73%) 
Vascular disorders     
Hypertension  1  12/109 (11.01%)  23/110 (20.91%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Ariad Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02094573     History of Changes
Other Study ID Numbers: AP26113-13-201
2013-002134-21 ( EudraCT Number )
First Submitted: March 18, 2014
First Posted: March 24, 2014
Results First Submitted: May 26, 2017
Results First Posted: June 21, 2017
Last Update Posted: October 3, 2017