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A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113)

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ClinicalTrials.gov Identifier: NCT01449461
Recruitment Status : Completed
First Posted : October 10, 2011
Results First Posted : June 21, 2017
Last Update Posted : March 4, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Lymphoma, Large-Cell, Anaplastic
Carcinoma, Non-Small-Cell Lung
Intervention Drug: Brigatinib
Enrollment 137
Recruitment Details Participants took part in the study at 9 investigative sites in the United States and Spain up to clinical cut-off date 16 November 2015. Study is ongoing.
Pre-assignment Details Participants with advanced malignancies, all histologies other than leukemia were enrolled in dose-escalation and participants with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements were enrolled in dose expansion phase. Participants received brigatinib 30 mg - 300 mg, tablets, orally once daily or twice daily.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months). 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. Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Period Title: Overall Study
Started 6 18 18 32 48 15
Completed 0 0 0 0 0 0
Not Completed 6 18 18 32 48 15
Reason Not Completed
Ongoing             0             6             2             15             17             2
Adverse Event             0             3             2             3             3             3
Death             0             1             0             0             4             1
Documented progressive disease             4             6             14             11             21             5
Clinical progressive disease             2             1             0             0             3             3
Reason not specified             0             1             0             3             0             1
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD Total
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months). 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. Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months). Total of all reporting groups
Overall Number of Baseline Participants 6 18 18 32 48 15 137
Hide Baseline Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
66.8  (9.30) 57.9  (12.93) 57.8  (10.91) 55.7  (11.41) 53.9  (11.10) 58.5  (15.60) 56.4  (12.02)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
18 - 64 years 2 11 12 25 39 9 98
≥65 years 4 7 6 7 9 6 39
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Female
3
  50.0%
6
  33.3%
5
  27.8%
18
  56.3%
19
  39.6%
7
  46.7%
58
  42.3%
Male
3
  50.0%
12
  66.7%
13
  72.2%
14
  43.8%
29
  60.4%
8
  53.3%
79
  57.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
American Indian or Alaska Native 0 0 0 1 1 0 2
Asian 0 4 3 3 5 2 17
Black or African American 0 1 2 0 1 1 5
Native Hawaiian or Other Pacific Islander 0 0 0 0 1 0 1
White 6 13 13 27 39 12 110
Unknown 0 0 0 0 1 0 1
Other 0 0 0 1 0 0 1
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Hispanic or Latino 1 0 0 1 1 0 3
Not Hispanic or Latino 5 18 18 31 47 15 134
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
United States 6 18 18 32 41 15 130
Spain 0 0 0 0 7 0 7
Eastern Cooperative Oncology Group (ECOG) Performance Score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
0 0 3 3 13 13 2 34
1 6 15 15 19 33 13 101
2 0 0 0 0 2 0 2
[1]
Measure Description: ECOG assessed participant's performance status on a 5 point scale: 0 equals (=) fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, but ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than [>] 50 percentage [%] of waking hours [h]), capable of all self care, but unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair and 5=Dead.
Time Since Diagnosis of Cancer  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
2.48  (3.303) 3.33  (2.184) 2.41  (1.346) 3.19  (2.726) 2.77  (2.053) 3.27  (1.913) 2.93  (2.192)
Participants with Diagnosis of Cancer Type  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
NSCLC 3 16 18 31 45 15 128
Other 3 2 0 1 3 0 9
Number of Participants with Mutation Types  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
anaplastic lymphoma kinase (ALK+) 1 16 6 29 27 5 84
Epidermal Growth Factor Receptor (EGFRm) 2 1 10 3 18 9 43
ROS proto-oncogene 1 (ROS1+) 0 0 0 0 3 1 4
Other 3 1 2 0 0 0 6
Participants with Prior Chemotherapy Regimen  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
0 0 2 7 12 12 3 36
1 3 4 3 6 17 2 35
2 0 9 4 8 10 5 36
> 2 3 3 4 6 9 5 30
Participants with Prior Radiotherapy to Brain  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
No 6 13 17 24 36 14 110
Yes 0 5 1 8 12 1 27
1.Primary Outcome
Title Recommended Phase 2 Dose of Brigatinib
Hide Description The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Arm/Group Title Brigatinib
Hide Arm/Group Description:
All participants who received brigatinib, tablets, orally, once daily in each cycle of 28 days.
Overall Number of Participants Analyzed 137
Mean (Full Range)
Unit of Measure: mg
NA [1] 
(90 to 180)
[1]
R2PD for this study is a dose range.
2.Primary Outcome
Title Objective Response Rate (ORR)
Hide Description ORR assessed by the investigator, is defined as the proportion of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 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 normalization 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. Crzb=Crizotinib.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all participants who received at least one dose of study drug. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here, n is the number of participants who were evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 1 14 6 28 25 5
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
With Prior Treatment with Crzb (n=1,13,5,25,23,4)
100.0
(2.5 to 100.0)
76.9
(46.2 to 95.0)
60.0
(14.7 to 94.7)
80.0
(59.3 to 93.2)
65.2
(42.7 to 83.6)
50.0
(6.8 to 93.2)
Without Prior Treatment with Crzb (n=0,1,1,3,2,1)
NA [1] 
(NA to NA)
100.0
(2.5 to 100.0)
100.0
(2.5 to 100.0)
100.0
(29.2 to 100.0)
100.0
(15.8 to 100.0)
100.0
(2.5 to 100.0)
[1]
No participant was analyzed in this arm
3.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 Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 6 18 18 32 48 15
Measure Type: Number
Unit of Measure: participants
6 18 18 31 48 15
4.Secondary Outcome
Title Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study
Hide Description The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of cycle 1). Evaluable participants must complete at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the MTD.
Time Frame Up to Cycle 1 (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug. MTD was not formally determined.
Arm/Group Title Dose Escalation Phase
Hide Arm/Group Description:
Participants received brigatinib tablets, orally, once daily (QD) starting at 30 mg in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: mg
NA [1] 
[1]
MTD criteria was not met.
5.Secondary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study
Hide Description DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting < 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC<500); Prolonged grade 4 neutropenia (> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle.
Time Frame Up to Cycle 1 (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 3 3 5 3 3 6 2
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 1 1
6.Secondary Outcome
Title Cmax: Maximum Observed Plasma Concentration for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participant analyzed is the participants who were evaluable for this outcome measure.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 3 3 50 11 44 10 2
Mean (Standard Deviation)
Unit of Measure: ng/mL
125.6  (41.07) 406.3  (102) 493  (289.5) 793.7  (828.7) 1185  (607.6) 1515  (637.9) 895 [1]   (NA)
[1]
Standard deviation was not calculated.
7.Secondary Outcome
Title Cmax: Maximum Observed Plasma Concentration for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 2 Day 2
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants who were evaluable for this outcome measure.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Mean (Standard Deviation)
Unit of Measure: ng/mL
249.50 [1]   (NA) 491.67  (223.95) 634.07  (310.05) 942.30  (472.33) 1694.3  (1014.3) 1694.3  (1014.3)
[1]
Standard deviation was not calculated.
8.Secondary Outcome
Title Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 3 3 50 11 44 10 2
Mean (Standard Deviation)
Unit of Measure: hours
3.9 [1]   (NA) 1.83  (1.9) 3.26  (4.53) 2.78  (1.7) 2.99  (3.77) 2.22  (1.02) 4.05 [1]   (NA)
[1]
Standard deviation was not calculated.
9.Secondary Outcome
Title Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Mean (Standard Deviation)
Unit of Measure: hour
2.49 [1]   (NA) 1.10  (0.656) 2.56  (1.98) 2.79  (1.88) 2.66  (1.46) 2.44  (1.13)
[1]
Standard deviation was not calculated.
10.Secondary Outcome
Title AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1, 8, 15 and 22 pre-dose and Day 1 multiple timepoints (up to 48 hours) post-dose; Cycle 2 Day 1 and 3 pre-dose and Day 1 multiple time points (up to 48 hours) post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 3 3 15 11 44 7 2
Mean (Standard Deviation)
Unit of Measure: h*ng/mL
1320.9  (576.29) 3900  (430.31) 5710.1  (3268.4) 9895.5  (11772) 13204  (6306.9) 16800  (7571.1) 7571.1 [1]   (NA)
[1]
Standard deviation was not calculated.
11.Secondary Outcome
Title Terminal Phase Elimination Half-life (T1/2) for Brigatinib
Hide Description [Not Specified]
Time Frame Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 2 3 15 10 63 7
Mean (Standard Deviation)
Unit of Measure: hours
31.55 [1]   (NA) 30.93  (5.873) 28.69  (10.06) 25.52  (7.958) 24.90  (7.437) 21.77  (4.007)
[1]
Standard deviation was not calculated.
12.Secondary Outcome
Title Best Overall Response
Hide Description Best overall response is defined as proportion of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. 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 normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 1 13 5 25 23 4
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Complete Response
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
8.0
(1.0 to 26.0)
8.7
(1.1 to 28.0)
0.0 [1] 
(NA to NA)
Partial Response
100
(2.5 to 100.0)
76.9
(46.2 to 95.0)
60.0
(14.7 to 94.7)
72.0
(50.6 to 87.9)
56.5
(34.5 to 76.8)
50.0
(6.8 to 93.2)
Stable Disease
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
8.0
(1.0 to 26.0)
13.0
(2.8 to 33.6)
50.0
(6.8 to 93.2)
Progressive Disease
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
0.0 [1] 
(NA to NA)
8.0
(1.0 to 26.0)
21.7
(7.5 to 43.7)
0 [1] 
(NA to NA)
[1]
95% CI was not estimable due to low number of participants with events.
13.Secondary Outcome
Title Duration of Response
Hide Description Duration of response is defined as time interval from the time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at 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 normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions. PD for target lesion: SLD increased by at least 20% from smallest value and must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS. Participants who were responders among those who were had anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here 'n' is participants analysed for each category. Duration of response was calculated by Kaplan-Meier estimation.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 1 13 5 25 23 4
Median (95% Confidence Interval)
Unit of Measure: months
With Prior Treatment with Crzb (n=1,10,3,20,15,2)
1.9 [1] 
(NA to NA)
8.3
(1.1 to 11.2)
4.0 [2] 
(3.7 to NA)
14.8 [2] 
(7.4 to NA)
9.9 [2] 
(3.6 to NA)
29.7 [1] 
(NA to NA)
Without Prior Treatment with Crzb (n=0,1,1,3,2,1)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(5.6 to NA)
NA [3] 
(9.2 to NA)
NA [3] 
(NA to NA)
[1]
Upper and lower limits of CI were not reached due to low number of participants with events.
[2]
Upper limit of CI was not reached due to low number of participants with events.
[3]
Median duration of response was not reached due to low number of participants with events.
14.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). PFS was calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here 'n' is participants analysed for each category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 1 13 5 25 23 4
Median (95% Confidence Interval)
Unit of Measure: months
With Prior Treatment with Crzb (n=1,9,4,13,14,3)
3.5 [1] 
(NA to NA)
11.9
(3.5 to 18.7)
5.7 [2] 
(0.5 to NA)
16.3 [2] 
(9.2 to NA)
10.8 [2] 
(4.5 to NA)
7.3
(1.9 to 31.5)
Without Prior Treatment with Crzb (n=0,0,0,1,1,0)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(7.4 to NA)
NA [3] 
(11.1 to NA)
NA [3] 
(NA to NA)
[1]
Upper and lower limit of CI was not reached due to low number of participants with events.
[2]
Upper limit of CI was not reached due to low number of participants with events.
[3]
Progression free survival was not reached due to low number of participants with events.
15.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.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 1 14 6 28 25 5
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(8.0 to 18.7)
NA [1] 
(NA to NA)
NA [1] 
(1.4 to 22.5)
NA [1] 
(0.2 to 17.6)
NA [1] 
(NA to NA)
[1]
Median overall survival was not reached due to low number of participants with events.
16.Secondary Outcome
Title Intracranial Objective Response Rate
Hide Description Intracranial objective response rate is defined as the proportion of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization 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. Meta.=Metastases.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure. Here, n is the number of participants who were evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Measurable Brain Metastases (n=0,2,0,5,7,1)
100
(15.8 to 100)
NA [1] 
(NA to NA)
80
(28.4 to 99.5)
42.9
(9.9 to 81.6)
100
(2.5 to 100)
Only Non-Measurable Brain Meta. (n=0,6,1,13,9,2)
16.7
(0.4 to 64.1)
100
(2.5 to 100)
46.2
(19.2 to 74.9)
44.4
(13.7 to 78.8)
50.0
(1.3 to 98.7)
[1]
No participant was evaluated for this arm.
17.Secondary Outcome
Title Duration of Intracranial Response
Hide Description Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Median (95% Confidence Interval)
Unit of Measure: months
12.9 [1] 
(NA to NA)
5.0 [1] 
(NA to NA)
11.4
(7.5 to 11.4)
29.2
(5.5 to 29.2)
11.3
(3.6 to 18.9)
[1]
Upper and Lower limit of duration of intracranial response was not reached due to low number of participants with events.
18.Secondary Outcome
Title Intracranial 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 in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
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.
Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Median (95% Confidence Interval)
Unit of Measure: months
36.8
(5.5 to 36.8)
6.7 [1] 
(NA to NA)
NA [2] 
(9.4 to NA)
14.4
(7.3 to 31.1)
7.3
(3.1 to 22.3)
[1]
Upper limit of CI was not reached due to low number of participants with events.
[2]
Progression-free survival was not reached due to low number of participants with events.
Time Frame Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 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 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months). 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. Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months). Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
All-Cause Mortality
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/6 (16.67%)   9/18 (50.00%)   10/18 (55.56%)   9/32 (28.13%)   25/48 (52.08%)   10/15 (66.67%) 
Cardiac disorders             
Atrial fibrillation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Supraventricular tachycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Cardiac failure congestive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cardiac tamponade  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Left ventricular dysfunction  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Tachycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Gastrointestinal disorders             
Pancreatitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Abdominal wall haematoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Bezoar  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Colitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Gastric ulcer haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Haemorrhoids  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal compression  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Rectal ulcer  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
General disorders             
Non-cardiac chest pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Pyrexia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Asthenia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Chest pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Death  1 [1]  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Influenza like illness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Sudden death  1 [2]  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Immune system disorders             
Food allergy  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Infections and infestations             
Pneumonia  1 [3]  0/6 (0.00%)  2/18 (11.11%)  3/18 (16.67%)  1/32 (3.13%)  3/48 (6.25%)  0/15 (0.00%) 
Bronchitis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Sepsis  1 [4]  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Device related infection  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Device related sepsis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Lower respiratory tract infection bacterial  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Pneumonia pseudomonal  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary tract infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Viral infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Injury, poisoning and procedural complications             
Post procedural haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Radiation necrosis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Radiation pneumonitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Investigations             
Alanine aminotransferase increased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Aspartate aminotransferase increased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Computerised tomogram thorax abnormal  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Metabolism and nutrition disorders             
Failure to thrive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hyperglycaemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Hyponatraemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Insulin resistance  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders             
Back pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Bone pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Intervertebral disc protrusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Muscular weakness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Pain in extremity  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Neoplasm progression  1 [5]  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  1/32 (3.13%)  4/48 (8.33%)  0/15 (0.00%) 
Pericardial effusion malignant  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  3/32 (9.38%)  0/48 (0.00%)  0/15 (0.00%) 
Metastases to central nervous system  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cancer pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Intracranial tumour haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Malignant ascites  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Metastatic malignant melanoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Metastatic pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Nervous system disorders             
Seizure  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Syncope  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Central nervous system haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cerebral haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cognitive disorder  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Embolic stroke  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haemorrhage intracranial  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haemorrhagic stroke  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Headache  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Ischaemic stroke  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Nervous system disorder  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Transient ischaemic attack  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Psychiatric disorders             
Mental status changes  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Confusional state  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Suicidal ideation  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Renal and urinary disorders             
Acute kidney injury  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Dyspnoea  1 [6]  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  4/15 (26.67%) 
Hypoxia  1 [2]  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  2/15 (13.33%) 
Pulmonary embolism  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Pneumonitis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Cough  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Respiratory failure  1 [7]  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Acute respiratory distress syndrome  1 [8]  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haemoptysis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Pneumothorax  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Skin and subcutaneous tissue disorders             
Eczema  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Rash  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Vascular disorders             
Haematoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
[1]
1 treatment-emergent death occurred during treatment with brigatinib 90 mg QD and is possibly related.
[2]
1 treatment-emergent death occurred during treatment with brigatinib 180 mg QD/90 mg BID and is possibly related.
[3]
1 treatment-emergent death occurred during treatment with brigatinib 120 mg QD/60 mg QD and 1 treatment-emergent death occurred during treatment with brigatinib 90 mg QD-180 mg QD and are not related
[4]
1 treatment-emergent death occurred during treatment with brigatinib 90 mg QD -180 mg QD/ and is possibly related.
[5]
8 treatment-emergent deaths occurred during treatment with brigatinib: 2; 90 mg QD, 1; 120 mg QD/60 mg BID, 1; 90 mg QD -180 mg QD and 4; 180 mg QD/90 mg BID and are not related.
[6]
1 treatment-emergent death occurred during treatment with brigatinib 240 mg QD/120 mg BID/ 300 mg QD and is not related.
[7]
1 treatment-emergent death occurred during treatment with brigatinib 180 mg QD/90 mg BID and is not related.
[8]
1 treatment-emergent death occurred during treatment with brigatinib 180 mg QD/ 90 mg BID and is not related.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   18/18 (100.00%)   17/18 (94.44%)   31/32 (96.88%)   44/48 (91.67%)   15/15 (100.00%) 
Blood and lymphatic system disorders             
Anaemia  1  0/6 (0.00%)  0/18 (0.00%)  4/18 (22.22%)  4/32 (12.50%)  2/48 (4.17%)  3/15 (20.00%) 
Increased tendency to bruise  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Leukocytosis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Cardiac disorders             
Sinus tachycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Palpitations  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Sinus bradycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Atrial fibrillation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Atrial flutter  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cardiac failure congestive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Ear and labyrinth disorders             
Tinnitus  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Deafness unilateral  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vertigo  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Endocrine disorders             
Hypothyroidism  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Eye disorders             
Vision blurred  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  4/32 (12.50%)  4/48 (8.33%)  0/15 (0.00%) 
Dry eye  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Visual impairment  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Blepharospasm  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Lacrimation increased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Photopsia  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vitreous floaters  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Asthenopia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Cataract cortical  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Colour blindness acquired  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Eye pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Eyelid margin crusting  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Gastrointestinal disorders             
Nausea  1  3/6 (50.00%)  6/18 (33.33%)  8/18 (44.44%)  14/32 (43.75%)  31/48 (64.58%)  8/15 (53.33%) 
Diarrhoea  1  1/6 (16.67%)  7/18 (38.89%)  7/18 (38.89%)  15/32 (46.88%)  18/48 (37.50%)  8/15 (53.33%) 
Constipation  1  1/6 (16.67%)  6/18 (33.33%)  5/18 (27.78%)  9/32 (28.13%)  7/48 (14.58%)  5/15 (33.33%) 
Vomiting  1  1/6 (16.67%)  1/18 (5.56%)  5/18 (27.78%)  5/32 (15.63%)  15/48 (31.25%)  5/15 (33.33%) 
Abdominal pain  1  3/6 (50.00%)  2/18 (11.11%)  3/18 (16.67%)  7/32 (21.88%)  9/48 (18.75%)  2/15 (13.33%) 
Dry mouth  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  4/32 (12.50%)  1/48 (2.08%)  2/15 (13.33%) 
Abdominal distension  1  0/6 (0.00%)  3/18 (16.67%)  1/18 (5.56%)  1/32 (3.13%)  4/48 (8.33%)  0/15 (0.00%) 
Abdominal discomfort  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  4/48 (8.33%)  0/15 (0.00%) 
Gastrooesophageal reflux disease  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  2/15 (13.33%) 
Dyspepsia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Dysphagia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  2/48 (4.17%)  2/15 (13.33%) 
Aphthous stomatitis  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Flatulence  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Sensitivity of teeth  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Stomatitis  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cheilitis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Mouth ulceration  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Abdominal rigidity  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Abnormal faeces  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Lip dry  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Lip swelling  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal irritation  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Toothache  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hypoaesthesia oral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
General disorders             
Fatigue  1  2/6 (33.33%)  9/18 (50.00%)  6/18 (33.33%)  13/32 (40.63%)  16/48 (33.33%)  12/15 (80.00%) 
Oedema peripheral  1  1/6 (16.67%)  1/18 (5.56%)  3/18 (16.67%)  6/32 (18.75%)  3/48 (6.25%)  5/15 (33.33%) 
Pyrexia  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  5/32 (15.63%)  6/48 (12.50%)  2/15 (13.33%) 
Pain  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  3/32 (9.38%)  3/48 (6.25%)  1/15 (6.67%) 
Chest discomfort  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  5/48 (10.42%)  2/15 (13.33%) 
Non-cardiac chest pain  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  1/32 (3.13%)  3/48 (6.25%)  3/15 (20.00%) 
Influenza like illness  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  3/48 (6.25%)  1/15 (6.67%) 
Asthenia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  5/48 (10.42%)  1/15 (6.67%) 
Chills  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Gait disturbance  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  3/48 (6.25%)  0/15 (0.00%) 
Peripheral swelling  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Chest pain  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Thirst  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Axillary pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Exercise tolerance decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Feeling abnormal  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Feeling jittery  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Immune system disorders             
Seasonal allergy  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  3/48 (6.25%)  0/15 (0.00%) 
Contrast media allergy  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Infections and infestations             
Upper respiratory tract infection  1  1/6 (16.67%)  0/18 (0.00%)  2/18 (11.11%)  7/32 (21.88%)  5/48 (10.42%)  3/15 (20.00%) 
Nasopharyngitis  1  0/6 (0.00%)  1/18 (5.56%)  3/18 (16.67%)  4/32 (12.50%)  5/48 (10.42%)  1/15 (6.67%) 
Urinary tract infection  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  3/32 (9.38%)  6/48 (12.50%)  1/15 (6.67%) 
Sinusitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  4/32 (12.50%)  1/48 (2.08%)  4/15 (26.67%) 
Pneumonia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  2/15 (13.33%) 
Bronchitis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  2/15 (13.33%) 
Influenza  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Oral candidiasis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Viral infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Vulvovaginal mycotic infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Conjunctivitis viral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Diarrhoea infectious  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Folliculitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Fungal skin infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Infectious pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Laryngitis viral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Lung infection  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Nail infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Nasal herpes  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Onychomycosis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Otitis externa  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Paronychia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Skin candida  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vaginal infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Injury, poisoning and procedural complications             
Laceration  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Rib fracture  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Procedural pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Radiation neuropathy  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Radiation pneumonitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Investigations             
Amylase increased  1  0/6 (0.00%)  4/18 (22.22%)  5/18 (27.78%)  9/32 (28.13%)  8/48 (16.67%)  3/15 (20.00%) 
Lipase increased  1  0/6 (0.00%)  3/18 (16.67%)  4/18 (22.22%)  10/32 (31.25%)  6/48 (12.50%)  2/15 (13.33%) 
Aspartate aminotransferase increased  1  0/6 (0.00%)  2/18 (11.11%)  6/18 (33.33%)  7/32 (21.88%)  7/48 (14.58%)  2/15 (13.33%) 
Alanine aminotransferase increased  1  0/6 (0.00%)  3/18 (16.67%)  3/18 (16.67%)  4/32 (12.50%)  4/48 (8.33%)  1/15 (6.67%) 
Blood insulin increased  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  3/32 (9.38%)  5/48 (10.42%)  0/15 (0.00%) 
Weight decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  3/48 (6.25%)  2/15 (13.33%) 
Blood creatinine increased  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  3/32 (9.38%)  1/48 (2.08%)  1/15 (6.67%) 
Lymphocyte count decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  2/48 (4.17%)  1/15 (6.67%) 
Weight increased  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  0/32 (0.00%)  3/48 (6.25%)  1/15 (6.67%) 
Blood alkaline phosphatase increased  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Blood testosterone decreased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  1/15 (6.67%) 
Blood thyroid stimulating hormone decreased  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Blood bilirubin increased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Blood lactate dehydrogenase increased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  1/15 (6.67%) 
Blood thyroid stimulating hormone increased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Activated partial thromboplastin time prolonged  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Electrocardiogram QT prolonged  1  2/6 (33.33%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Bacterial test positive  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Ejection fraction decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Heart rate increased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary sediment present  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Urine leukocyte esterase positive  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
White blood cells urine  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
White blood cells urine positive  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Metabolism and nutrition disorders             
Decreased appetite  1  0/6 (0.00%)  5/18 (27.78%)  1/18 (5.56%)  8/32 (25.00%)  9/48 (18.75%)  5/15 (33.33%) 
Hypophosphataemia  1  0/6 (0.00%)  0/18 (0.00%)  2/18 (11.11%)  6/32 (18.75%)  3/48 (6.25%)  2/15 (13.33%) 
Hypomagnesaemia  1  0/6 (0.00%)  0/18 (0.00%)  3/18 (16.67%)  2/32 (6.25%)  2/48 (4.17%)  4/15 (26.67%) 
Hypokalaemia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  2/48 (4.17%)  3/15 (20.00%) 
Hyponatraemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  1/48 (2.08%)  1/15 (6.67%) 
Dehydration  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Hyperglycaemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Increased appetite  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Hyperlipidaemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hypernatraemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  1/48 (2.08%)  1/15 (6.67%) 
Musculoskeletal and connective tissue disorders             
Muscle spasms  1  1/6 (16.67%)  1/18 (5.56%)  3/18 (16.67%)  7/32 (21.88%)  11/48 (22.92%)  3/15 (20.00%) 
Back pain  1  1/6 (16.67%)  0/18 (0.00%)  5/18 (27.78%)  7/32 (21.88%)  7/48 (14.58%)  1/15 (6.67%) 
Musculoskeletal pain  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  2/32 (6.25%)  4/48 (8.33%)  3/15 (20.00%) 
Arthralgia  1  1/6 (16.67%)  3/18 (16.67%)  0/18 (0.00%)  10/32 (31.25%)  6/48 (12.50%)  0/15 (0.00%) 
Pain in extremity  1  1/6 (16.67%)  2/18 (11.11%)  2/18 (11.11%)  2/32 (6.25%)  2/48 (4.17%)  2/15 (13.33%) 
Musculoskeletal chest pain  1  2/6 (33.33%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  3/48 (6.25%)  1/15 (6.67%) 
Joint swelling  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  5/32 (15.63%)  2/48 (4.17%)  0/15 (0.00%) 
Myalgia  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Bone pain  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  5/48 (10.42%)  0/15 (0.00%) 
Musculoskeletal discomfort  1  0/6 (0.00%)  0/18 (0.00%)  2/18 (11.11%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Flank pain  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Muscular weakness  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Pain in jaw  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Arthritis  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Fracture pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Limb discomfort  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Musculoskeletal stiffness  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Groin pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neck pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Osteopenia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Pericardial effusion malignant  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Melanocytic naevus  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Skin papilloma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Tumour pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Nervous system disorders             
Headache  1  0/6 (0.00%)  7/18 (38.89%)  7/18 (38.89%)  12/32 (37.50%)  14/48 (29.17%)  6/15 (40.00%) 
Dizziness  1  0/6 (0.00%)  4/18 (22.22%)  1/18 (5.56%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Peripheral sensory neuropathy  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  5/32 (15.63%)  3/48 (6.25%)  0/15 (0.00%) 
Paraesthesia  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  3/48 (6.25%)  1/15 (6.67%) 
Dysgeusia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  3/48 (6.25%)  1/15 (6.67%) 
Tremor  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  2/48 (4.17%)  1/15 (6.67%) 
Amnesia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  3/48 (6.25%)  0/15 (0.00%) 
Balance disorder  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  0/32 (0.00%)  3/48 (6.25%)  0/15 (0.00%) 
Hypoaesthesia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  3/48 (6.25%)  1/15 (6.67%) 
Visual field defect  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  4/48 (8.33%)  1/15 (6.67%) 
Seizure  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Aphasia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Disturbance in attention  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Dysarthria  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Memory impairment  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Sinus headache  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Somnolence  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Syncope  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Burning sensation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cognitive disorder  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neuralgia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Parosmia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Peripheral motor neuropathy  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Psychiatric disorders             
Insomnia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  6/32 (18.75%)  3/48 (6.25%)  3/15 (20.00%) 
Anxiety  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  4/32 (12.50%)  1/48 (2.08%)  1/15 (6.67%) 
Depression  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  3/32 (9.38%)  3/48 (6.25%)  0/15 (0.00%) 
Bruxism  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Anticipatory anxiety  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Confusional state  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Disorientation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Nervousness  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Stress  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Renal and urinary disorders             
Pollakiuria  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  4/48 (8.33%)  0/15 (0.00%) 
Proteinuria  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Haematuria  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Dysuria  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Renal failure  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary retention  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Reproductive system and breast disorders             
Vulvovaginal dryness  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Nipple pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  1/6 (16.67%)  6/18 (33.33%)  6/18 (33.33%)  11/32 (34.38%)  13/48 (27.08%)  8/15 (53.33%) 
Dyspnoea  1  0/6 (0.00%)  2/18 (11.11%)  5/18 (27.78%)  7/32 (21.88%)  7/48 (14.58%)  3/15 (20.00%) 
Dyspnoea exertional  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  1/32 (3.13%)  4/48 (8.33%)  1/15 (6.67%) 
Oropharyngeal pain  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  2/32 (6.25%)  4/48 (8.33%)  1/15 (6.67%) 
Epistaxis  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  1/32 (3.13%)  4/48 (8.33%)  2/15 (13.33%) 
Productive cough  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  2/48 (4.17%)  0/15 (0.00%) 
Nasal congestion  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Haemoptysis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Hypoxia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Rhinorrhoea  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  0/15 (0.00%) 
Sinus congestion  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  0/48 (0.00%)  0/15 (0.00%) 
Dysphonia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Rhinitis allergic  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Sputum discoloured  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Dry throat  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Hiccups  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Laryngeal inflammation  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Pleuritic pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Throat irritation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Wheezing  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Nasal dryness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Pleurisy  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Pneumothorax  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Pulmonary hypertension  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Respiratory tract irritation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Sneezing  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Upper-airway cough syndrome  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Skin and subcutaneous tissue disorders             
Rash  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  4/32 (12.50%)  7/48 (14.58%)  1/15 (6.67%) 
Photosensitivity reaction  1  0/6 (0.00%)  0/18 (0.00%)  4/18 (22.22%)  3/32 (9.38%)  5/48 (10.42%)  0/15 (0.00%) 
Pruritus  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  6/32 (18.75%)  3/48 (6.25%)  0/15 (0.00%) 
Dry skin  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  4/32 (12.50%)  3/48 (6.25%)  0/15 (0.00%) 
Night sweats  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  0/32 (0.00%)  4/48 (8.33%)  0/15 (0.00%) 
Dermatitis acneiform  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  1/48 (2.08%)  0/15 (0.00%) 
Alopecia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  3/48 (6.25%)  1/15 (6.67%) 
Hyperhidrosis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Onychoclasis  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Rash pruritic  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Dermatitis contact  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Eczema  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Erythema  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Pain of skin  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Skin disorder  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Dermal cyst  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Dermatitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Dermatitis atopic  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Nail disorder  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Petechiae  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Skin hyperpigmentation  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Urticaria  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Nail growth abnormal  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vascular disorders             
Hypertension  1  0/6 (0.00%)  1/18 (5.56%)  5/18 (27.78%)  7/32 (21.88%)  6/48 (12.50%)  1/15 (6.67%) 
Hypotension  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  1/15 (6.67%) 
Deep vein thrombosis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vascular pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
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: Takeda ( Ariad Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01449461    
Other Study ID Numbers: AP26113-11-101
2011-005718-12 ( EudraCT Number )
U1111-1196-8197 ( Other Identifier: World Health Organization )
First Submitted: September 30, 2011
First Posted: October 10, 2011
Results First Submitted: May 26, 2017
Results First Posted: June 21, 2017
Last Update Posted: March 4, 2020