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)

Sponsor
Ariad Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01449461
Collaborator
(none)
137
6
101

Study Details

Study Description

Brief Summary

The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered brigatinib, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of brigatinib, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which brigatinib is active.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

The drug being tested in this study is called brigatinib (AP26113). Brigatinib is being tested to treat people with NSCLC. This study will look at the safety, tolerability and efficacy of brigatinib.

The study enrolled 137 patients. Participants were assigned to one of the following treatment groups:

  • Brigatinib 30 mg once daily (QD)/60 mg QD

  • Brigatinib 90 mg QD

  • Brigatinib 120 mg QD/60 mg twice daily (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

This multi-center trial will be conducted worldwide. The overall expected time to participate in this study is approximately 4 years. Participants will make multiple visits to the clinic, and 30 days after the End-of-Treatment visit. Follow-up is intended to continue for at least 2 years after the initial dose.

Study Design

Study Type:
Interventional
Actual Enrollment :
137 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
Actual Study Start Date :
Sep 20, 2011
Actual Primary Completion Date :
Nov 16, 2015
Actual Study Completion Date :
Feb 18, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Brigatinib 30 mg QD/60 mg QD

Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).

Drug: Brigatinib
Brigatinib tablets and capsules.
Other Names:
  • ALUNBRIG™
  • AP26113
  • Experimental: Brigatinib 90 mg QD

    Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).

    Drug: Brigatinib
    Brigatinib tablets and capsules.
    Other Names:
  • ALUNBRIG™
  • AP26113
  • Experimental: Brigatinib 120 mg QD/60 mg BID

    Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).

    Drug: Brigatinib
    Brigatinib tablets and capsules.
    Other Names:
  • ALUNBRIG™
  • AP26113
  • Experimental: Brigatinib 90 mg QD-180 mg QD

    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.

    Drug: Brigatinib
    Brigatinib tablets and capsules.
    Other Names:
  • ALUNBRIG™
  • AP26113
  • Experimental: Brigatinib 180 mg QD/90 mg BID

    Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).

    Drug: Brigatinib
    Brigatinib tablets and capsules.
    Other Names:
  • ALUNBRIG™
  • AP26113
  • Experimental: Brigatinib 240 mg QD/120 mg BID/300 mg QD

    Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).

    Drug: Brigatinib
    Brigatinib tablets and capsules.
    Other Names:
  • ALUNBRIG™
  • AP26113
  • Outcome Measures

    Primary Outcome Measures

    1. Recommended Phase 2 Dose (RP2D) of Brigatinib [28 days]

      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).

    2. Objective Response Rate (ORR) [From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)]

      ORR assessed by the investigator, is defined as the percentage 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.

    Secondary Outcome Measures

    1. Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE) [From first dose of study drug up to 30 days following the last dose of the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)]

      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.

    2. Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study [Up to Cycle 1 (28 days)]

      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).

    3. Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study [Up to Cycle 1 (28 days)]

      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.

    4. Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 1 Day 1 [Cycle 1 (28-days cycle): Day 1]

    5. Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 2 Day 1 [Cycle 2 (28-days cycle): Day 1]

    6. Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 1 Day 1 [Cycle 1 (28-days cycle): Day 1]

    7. Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1 [Cycle 2 (28-days cycle): Day 1]

    8. AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 1 Day 1 [Cycle 1 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose]

    9. AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 2 Day 1 [Cycle 2 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose]

    10. T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1 [Cycle 2 (28-days cycle): Day 1]

    11. Best Overall Response [Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)]

      Best overall response is defined as percentage 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.

    12. Duration of Response [Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)]

      Duration of response is defined as time interval from 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 >=5 mm or development of any new lesion.PD for non-target lesion:unequivocal progression of existing non-target lesions.Duration of response calculated by Kaplan-Meier estimation.

    13. Progression Free Survival (PFS) [Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)]

      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).

    14. Overall Survival (OS) [Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)]

      OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause.

    15. Intracranial Objective Response Rate [Screening and at 8-week intervals thereafter (approximately up to 50 months)]

      Intracranial objective response rate is defined as the percentage 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.

    16. Duration of Intracranial Response [Screening and at 8-week intervals thereafter (approximately up to 50 months)]

      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.

    17. Intracranial Progression Free Survival (PFS) [Screening and at 8-week intervals thereafter (approximately up to 50 months)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    General Eligibility Criteria

    1. All participants must have tumor tissue available for analysis. If sufficient tissue is not available, participants must undergo a biopsy to obtain adequate samples. For participants in expansion cohorts 2, 3 and 5, for whom failure of prior therapy is specified (crizotinib for cohorts 2 and 5, one epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for cohort 3), tumor tissue must be available following failure of the prior therapy.

    2. Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).

    3. Male or female participants ≥ 18 years old.

    4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

    5. Minimum life expectancy of 3 months or more.

    6. Adequate renal and hepatic function.

    7. Adequate bone marrow function.

    8. Normal QT interval on screening electrocardiogram (ECG) evaluation.

    9. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

    10. Female participants who are of childbearing potential and fertile male participants must agree to use an effective form of contraception with their sexual partners throughout study participation.

    11. Signed and dated informed consent indicating that the participant has been informed of all pertinent aspects of the study.

    12. Willingness and ability to comply with scheduled visits and study procedures.

    Cohort-specific Eligibility Criteria

    PART 1: Dose Escalation Phase:
    1. Histologically confirmed advanced malignancies. All histologies except leukemia;

    2. Refractory to available therapies or for whom no standard or available curative treatments exist;

    3. Tumor tissue available for analysis.

    PART 2: Expansion cohorts (5 additional cohorts):
    1. Expansion cohort 1: Non-small cell lung cancer (NSCLC) participants whose tumors exhibit anaplastic lymphoma kinase (ALK) rearrangements and who have not been treated with previous ALK inhibitors.
    1. Histologically or cytologically confirmed NSCLC; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1; iii. History of ALK rearrangement by fluorescence in situ hybridization (FISH); iv. No prior ALK inhibitor therapy; 2. Expansion cohort 2: NSCLC participants whose tumors exhibit ALK rearrangements and who are resistant to crizotinib:
    2. Histologically or cytologically confirmed NSCLC; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1); iii. History of ALK rearrangement by FISH; iv. Resistant to crizotinib (and have not received any other prior ALK inhibitor therapy); 3. Expansion cohort 3: NSCLC participants whose tumors exhibit an epidermal growth factor receptor EGFR-T790M mutation and who are resistant to 1 prior EGFR TKI: i. Histologically or cytologically confirmed NSCLC ii. Previous treatment with only 1 EGFR TKI for which the last administration was within 30 days of the initiation of brigatinib; iii. Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy; iv. No intervening systemic therapy between cessation of the EGFR TKI and initiating brigatinib; v. Tumor tissue available for analysis (see General Eligibility Criterion 1). 4. Expansion cohort 4: Participants with any cancers with abnormalities in ALK or other brigatinib targets. Examples include, but are not limited to, anaplastic large cell lymphoma (ALCL), diffuse large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors (IMT), and other cancers with ALK abnormalities, or tumors with ROS1 fusions: i. Histologically confirmed lymphomas and other cancers, with the exception of leukemias; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1). 5. Expansion Cohort 5: NSCLC participants whose tumors exhibit ALK rearrangements and who have active, measurable brain metastases: i. Histologically or cytologically confirmed NSCLC: ii. Tumor tissue available for analysis (see General Eligibility Criterion 1); iii. History of ALK rearrangement by FISH; iv. Either crizotinib naive or resistant; v. Have at least one measurable brain lesion (≥ 10 mm by contrast enhanced, T1 weighted magnetic resonance imaging [cMRI]). Previously treated brain lesions by stereotactic radiosurgery (SRS) or surgical resection should not be included as a target or non-target lesion; vi. Previously untreated brain metastases with radiologically documented new or progressing brain lesions. Unequivocal progression of previously treated lesions (non-SRS and non-surgically treated lesions) at least 3 months after the last treatment; vii. Neurologically stable. Participants must be on a stable or deceasing dose of corticosteroids and/or have no requirement for anticonvulsants for 5 days prior to the baseline MRI and for 5 days prior to initiating brigatinib.
    Exclusion Criteria:
    1. Received an investigational agent ≤ 14 days prior to initiating brigatinib.

    2. Received systemic anticancer therapy (including monoclonal antibodies and irreversible TKIs such as afatinib or dacomitinib) or radiation therapy ≤ 14 days prior to initiating brigatinib.

    1. Except for a reversible TKI (ie, erlotinib or gefitinib) or crizotinib, which are allowed up to 72 hours prior to initiating brigatinib, provided that the participant is free of treatment-related toxicity that might confound the safety evaluation of brigatinib.
    1. Received any prior agents targeted against ALK, with the exception of crizotinib, or received more than 1 prior EGFR TKI.
    1. Re-challenge with the same TKI is allowed.
    1. Major surgery within 28 days prior to initiating brigatinib.

    2. Brain metastases that are neurologically unstable or require anticonvulsants or an increasing dose of corticosteroids.

    3. Participants with previously treated brain metastases without evidence of disease or recurrence are allowed for cohorts 1-4.

    4. Participants with evaluable but non-measurable, active brain lesions who otherwise meet the criteria for cohort 5 for CNS disease can be enrolled in other cohorts.

    5. Significant uncontrolled or active cardiovascular disease.

    6. Uncontrolled hypertension (diastolic blood pressure [BP] > 100 mm Hg; systolic > 150 mm Hg).

    7. Prolonged QT interval, or being treated with medications known to cause Torsades de Pointes.

    8. History or presence of pulmonary interstitial disease or drug-related pneumonitis.

    9. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.

    10. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.

    11. Pregnant or breastfeeding.

    12. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of brigatinib.

    13. Any condition or illness that, in the opinion of the Investigator, would compromise participant safety or interfere with the evaluation of the safety of the drug.

    14. Leptomeningeal carcinomatosis and spinal cord compression. In the case of suspected meningeal involvement, a negative lumbar puncture prior to study entry is required.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Ariad Pharmaceuticals

    Investigators

    • Study Director: Medical Director, Takeda

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Ariad Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01449461
    Other Study ID Numbers:
    • AP26113-11-101
    • 2011-005718-12
    • U1111-1196-8197
    First Posted:
    Oct 10, 2011
    Last Update Posted:
    Aug 17, 2021
    Last Verified:
    Jul 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 9 investigative sites in the United States and Spain from 20 September 2011 to 18 February 2020.
    Pre-assignment Detail 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    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

    Baseline Characteristics

    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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Total of all reporting groups
    Overall Participants 6 18 18 32 48 15 137
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    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 (Count of Participants)
    Adults [18-64 years]
    2
    33.3%
    11
    61.1%
    12
    66.7%
    25
    78.1%
    39
    81.3%
    9
    60%
    98
    71.5%
    From 65 to 84 years
    4
    66.7%
    7
    38.9%
    6
    33.3%
    7
    21.9%
    9
    18.8%
    6
    40%
    39
    28.5%
    Sex: Female, Male (Count of Participants)
    Female
    3
    50%
    12
    66.7%
    13
    72.2%
    14
    43.8%
    29
    60.4%
    8
    53.3%
    79
    57.7%
    Male
    3
    50%
    6
    33.3%
    5
    27.8%
    18
    56.3%
    19
    39.6%
    7
    46.7%
    58
    42.3%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    1
    3.1%
    1
    2.1%
    0
    0%
    2
    1.5%
    Asian
    0
    0%
    4
    22.2%
    3
    16.7%
    3
    9.4%
    5
    10.4%
    2
    13.3%
    17
    12.4%
    Black or African American
    0
    0%
    1
    5.6%
    2
    11.1%
    0
    0%
    1
    2.1%
    1
    6.7%
    5
    3.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    0
    0%
    1
    0.7%
    White
    6
    100%
    13
    72.2%
    13
    72.2%
    27
    84.4%
    39
    81.3%
    12
    80%
    110
    80.3%
    Unknown
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    0
    0%
    1
    0.7%
    Other
    0
    0%
    0
    0%
    0
    0%
    1
    3.1%
    0
    0%
    0
    0%
    1
    0.7%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic or Latino
    1
    16.7%
    0
    0%
    0
    0%
    1
    3.1%
    1
    2.1%
    0
    0%
    3
    2.2%
    Not Hispanic or Latino
    5
    83.3%
    18
    100%
    18
    100%
    31
    96.9%
    47
    97.9%
    15
    100%
    134
    97.8%
    Region of Enrollment (Count of Participants)
    United States
    6
    100%
    18
    100%
    18
    100%
    32
    100%
    41
    85.4%
    15
    100%
    130
    94.9%
    Spain
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    7
    14.6%
    0
    0%
    7
    5.1%
    Eastern Cooperative Oncology Group (ECOG) Performance Score (Count of Participants)
    0
    0
    0%
    3
    16.7%
    3
    16.7%
    13
    40.6%
    13
    27.1%
    2
    13.3%
    34
    24.8%
    1
    6
    100%
    15
    83.3%
    15
    83.3%
    19
    59.4%
    33
    68.8%
    13
    86.7%
    101
    73.7%
    2
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    4.2%
    0
    0%
    2
    1.5%
    Time Since Diagnosis of Cancer (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    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 (Count of Participants)
    NSCLC
    3
    50%
    16
    88.9%
    18
    100%
    31
    96.9%
    45
    93.8%
    15
    100%
    128
    93.4%
    Other
    3
    50%
    2
    11.1%
    0
    0%
    1
    3.1%
    3
    6.3%
    0
    0%
    9
    6.6%
    Number of Participants with Mutation Types (Count of Participants)
    Anaplastic Lymphoma Kinase (ALK+)
    1
    16.7%
    16
    88.9%
    6
    33.3%
    29
    90.6%
    27
    56.3%
    5
    33.3%
    84
    61.3%
    Epidermal Growth Factor Receptor (EGFRm)
    2
    33.3%
    1
    5.6%
    10
    55.6%
    3
    9.4%
    18
    37.5%
    9
    60%
    43
    31.4%
    ROS Proto-oncogene 1 (ROS1+)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    6.3%
    1
    6.7%
    4
    2.9%
    Other
    3
    50%
    1
    5.6%
    2
    11.1%
    0
    0%
    0
    0%
    0
    0%
    6
    4.4%
    Participants with Prior Chemotherapy Regimen (Count of Participants)
    0
    0
    0%
    2
    11.1%
    7
    38.9%
    12
    37.5%
    12
    25%
    3
    20%
    36
    26.3%
    1
    3
    50%
    4
    22.2%
    3
    16.7%
    6
    18.8%
    17
    35.4%
    2
    13.3%
    35
    25.5%
    2
    0
    0%
    9
    50%
    4
    22.2%
    8
    25%
    10
    20.8%
    5
    33.3%
    36
    26.3%
    > 2
    3
    50%
    3
    16.7%
    4
    22.2%
    6
    18.8%
    9
    18.8%
    5
    33.3%
    30
    21.9%
    Participants with Prior Radiotherapy to Brain (Count of Participants)
    No
    6
    100%
    13
    72.2%
    17
    94.4%
    24
    75%
    36
    75%
    14
    93.3%
    110
    80.3%
    Yes
    0
    0%
    5
    27.8%
    1
    5.6%
    8
    25%
    12
    25%
    1
    6.7%
    27
    19.7%

    Outcome Measures

    1. Primary Outcome
    Title Recommended Phase 2 Dose (RP2D) of Brigatinib
    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

    Outcome Measure Data

    Analysis Population Description
    Safety population included all enrolled participants who received at least one dose of study drug.
    Arm/Group Title Brigatinib
    Arm/Group Description All participants who received brigatinib, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 137
    Mean (Full Range) [mg]
    NA
    2. Primary Outcome
    Title Objective Response Rate (ORR)
    Description ORR assessed by the investigator, is defined as the percentage 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 From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)

    Outcome Measure Data

    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. Number analyzed is the number of participants with data 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 1 14 6 28 25 5
    With Prior Treatment with Crizotinib
    0
    0%
    53.8
    298.9%
    60.0
    333.3%
    76.0
    237.5%
    65.2
    135.8%
    25.0
    166.7%
    Without Prior Treatment with Crizotinib
    100.0
    1666.7%
    100.0
    555.6%
    100.0
    555.6%
    100.0
    312.5%
    100.0
    208.3%
    3. Secondary Outcome
    Title Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
    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 the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)

    Outcome Measure Data

    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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 6 18 18 32 48 15
    Count of Participants [Participants]
    6
    100%
    18
    100%
    18
    100%
    32
    100%
    48
    100%
    15
    100%
    4. Secondary Outcome
    Title Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study
    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).
    Time Frame Up to Cycle 1 (28 days)

    Outcome Measure Data

    Analysis Population Description
    Safety population included all enrolled participants who received at least one dose of study drug. Participants enrolled in the dose escalation phase were included in the analysis.
    Arm/Group Title Brigatinib
    Arm/Group Description All participants received brigatinib tablets, orally, once daily (QD) starting at 30 mg in each cycle of 28 days.
    Measure Participants 66
    Number [mg]
    NA
    5. Secondary Outcome
    Title Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study
    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)

    Outcome Measure Data

    Analysis Population Description
    DLT-evaluable population included participants who received ≥75% of planned study drug doses during Cycle 1.
    Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 3 3 5 3 3 6 2
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    6.7%
    1
    0.7%
    6. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 1 Day 1
    Description
    Time Frame Cycle 1 (28-days cycle): Day 1

    Outcome Measure Data

    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. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 3 3 50 11 44 10 2
    Mean (Standard Deviation) [ng/mL]
    125.6
    (41.07)
    406.3
    (102)
    493
    (289.5)
    793.7
    (828.7)
    1185
    (607.6)
    1515
    (637.9)
    895
    (487.9)
    7. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 2 Day 1
    Description
    Time Frame Cycle 2 (28-days cycle): Day 1

    Outcome Measure Data

    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 with data available for analysis for this outcome measure. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 2 3 15 10 63 7 0
    Mean (Standard Deviation) [ng/mL]
    249.50
    (167.58)
    491.67
    (223.95)
    634.07
    (310.05)
    942.30
    (472.33)
    1694.3
    (1014.3)
    2280.0
    (1308.5)
    8. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 1 Day 1
    Description
    Time Frame Cycle 1 (28-days cycle): Day 1

    Outcome Measure Data

    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. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 3 3 50 11 44 10 2
    Median (Full Range) [hours]
    3.9
    1.0
    2.0
    2.0
    2.0
    2.0
    4.05
    9. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1
    Description
    Time Frame Cycle 2 (28-days cycle): Day 1

    Outcome Measure Data

    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 with data available for analyses for this outcome measure. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 2 3 15 10 63 7 0
    Median (Full Range) [hours]
    2.49
    1.00
    2.00
    3.00
    2.10
    2.00
    10. Secondary Outcome
    Title AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 1 Day 1
    Description
    Time Frame Cycle 1 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose

    Outcome Measure Data

    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. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 3 3 15 11 63 7 2
    Mean (Standard Deviation) [h*ng/mL]
    1320.9
    (576.29)
    3900
    (430.31)
    5710.1
    (3268.4)
    9895.5
    (11772)
    13204
    (6306.9)
    16800
    (7571.1)
    12356
    (5869)
    11. Secondary Outcome
    Title AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 2 Day 1
    Description
    Time Frame Cycle 2 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose

    Outcome Measure Data

    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 with data available for analyses for this outcome measure. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 2 3 15 10 63 7 0
    Mean (Standard Deviation) [h*ng/mL]
    2689.0
    (1145.5)
    5069.0
    (1664.7)
    9142.1
    (4076.7)
    13888
    (7011.4)
    23478
    (14463)
    30117
    (19921)
    12. Secondary Outcome
    Title T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1
    Description
    Time Frame Cycle 2 (28-days cycle): Day 1

    Outcome Measure Data

    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 with data available for analyses for this outcome measure. 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
    Arm/Group Description Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 2 3 15 10 63 7 0
    Mean (Standard Deviation) [hours]
    31.55
    (2.758)
    30.93
    (5.873)
    28.69
    (10.06)
    25.52
    (7.958)
    24.90
    (7.437)
    21.77
    (4.007)
    13. Secondary Outcome
    Title Best Overall Response
    Description Best overall response is defined as percentage 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 end of the study (up to 8.4 years)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all participants who received at least one dose of study drug. Participants with ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 1 14 6 28 25 5
    With Prior Treatment with Crizotinib: Complete Response
    0.0
    0%
    0.0
    0%
    0.0
    0%
    12.0
    37.5%
    8.7
    18.1%
    0.0
    0%
    Without Prior Treatment with Crizotinib: Complete Response
    0.0
    0%
    100.0
    555.6%
    33.3
    185%
    0.0
    0%
    100.0
    208.3%
    With Prior Treatment with Crizotinib: Partial Response
    0.0
    0%
    53.8
    298.9%
    60.0
    333.3%
    64.0
    200%
    56.5
    117.7%
    25.0
    166.7%
    Without Prior Treatment with Crizotinib: Partial Response
    100.0
    1666.7%
    0.0
    0%
    66.7
    370.6%
    100.0
    312.5%
    0.0
    0%
    With Prior Treatment with Crizotinib: Stable Disease
    100.0
    1666.7%
    23.1
    128.3%
    0.0
    0%
    12.0
    37.5%
    13.0
    27.1%
    75.0
    500%
    Without Prior Treatment with Crizotinib: Stable Disease
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    With Prior Treatment with Crizotinib: Progressive Disease
    0.0
    0%
    0.0
    0%
    0.0
    0%
    8.0
    25%
    21.7
    45.2%
    0.0
    0%
    Without Prior Treatment with Crizotinib: Progressive Disease
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    14. Secondary Outcome
    Title Duration of Response
    Description Duration of response is defined as time interval from 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 >=5 mm or development of any new lesion.PD for non-target lesion:unequivocal progression of existing non-target lesions.Duration of response calculated by Kaplan-Meier estimation.
    Time Frame Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all participants who received at least one dose of study drug. Participants who were responders among those who had ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 0 8 4 22 17 2
    With Prior Treatment with Crizotinib
    11.1
    4.0
    14.8
    20.4
    29.7
    Without Prior Treatment with Crizotinib
    30.4
    60.3
    52.0
    20.8
    NA
    15. Secondary Outcome
    Title Progression Free Survival (PFS)
    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 Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, overall number of participants analyzed is the participants who were evaluable 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 5 15 17 21 40 7
    Median (95% Confidence Interval) [months]
    1.8
    12.6
    5.4
    11.0
    5.4
    5.4
    16. Secondary Outcome
    Title Overall Survival (OS)
    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 end of the study (up to 8.4 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, overall number of participants analyzed is the participants who were evaluable 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 6 11 12 17 25 11
    Median (95% Confidence Interval) [months]
    5.3
    11.6
    7.3
    17.9
    7.3
    8.3
    17. Secondary Outcome
    Title Intracranial Objective Response Rate
    Description Intracranial objective response rate is defined as the percentage 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.
    Time Frame Screening and at 8-week intervals thereafter (approximately up to 50 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure. Here, number analyzed 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 0 8 1 18 16 3
    Measurable Brain Metastases
    100
    1666.7%
    80
    444.4%
    42.9
    238.3%
    100
    312.5%
    Only Non-Measurable Brain Metastases
    16.7
    278.3%
    100
    555.6%
    46.2
    256.7%
    44.4
    138.8%
    50.0
    104.2%
    18. Secondary Outcome
    Title Duration of Intracranial Response
    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 (approximately up to 50 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set. ALK+ NSCLC participants with measurable and 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 0 8 1 18 16 3
    Median (95% Confidence Interval) [months]
    12.9
    5.0
    11.4
    29.2
    11.3
    19. Secondary Outcome
    Title Intracranial Progression Free Survival (PFS)
    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 (approximately up to 50 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set. ALK+ NSCLC participants with measurable and 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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    Measure Participants 0 8 1 18 16 3
    Median (95% Confidence Interval) [months]
    36.8
    6.7
    NA
    14.4
    7.3

    Adverse Events

    Time Frame All-Cause Mortality: From first dose up to the End of the Study (Up to 8.4 years). Serious and other adverse events: From first dose of study drug up to 30 days following the last dose of the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)
    Adverse Event Reporting Description
    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
    Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 11/18 (61.1%) 12/18 (66.7%) 17/32 (53.1%) 25/48 (52.1%) 11/15 (73.3%)
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/6 (16.7%) 10/18 (55.6%) 10/18 (55.6%) 14/32 (43.8%) 30/48 (62.5%) 11/15 (73.3%)
    Cardiac disorders
    Atrial fibrillation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Supraventricular tachycardia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Cardiac failure congestive 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cardiac tamponade 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Angina unstable 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Tachycardia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Cardio-respiratory arrest 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Pericardial effusion 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Eye disorders
    Blindness 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Gastrointestinal disorders
    Pancreatitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 1/15 (6.7%)
    Abdominal wall haematoma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Bezoar 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Colitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Gastric ulcer haemorrhage 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Haemorrhoids 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Oesophageal compression 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Rectal ulcer 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Intestinal obstruction 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    General disorders
    Non-cardiac chest pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 1/15 (6.7%)
    Pyrexia 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 1/15 (6.7%)
    Death 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Influenza like illness 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Sudden death 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Immune system disorders
    Food allergy 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Infections and infestations
    Pneumonia 0/6 (0%) 2/18 (11.1%) 3/18 (16.7%) 1/32 (3.1%) 4/48 (8.3%) 0/15 (0%)
    Bronchitis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Sepsis 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Device related infection 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Device related sepsis 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Atypical mycobacterial lower respiratory tract infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Pneumonia pseudomonal 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Urinary tract infection 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Viral infection 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Cellulitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Respiratory tract infection 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Injury, poisoning and procedural complications
    Post procedural haemorrhage 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Radiation necrosis 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Radiation pneumonitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Femur fracture 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Radiation associated cardiac failure 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Road traffic accident 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Investigations
    Alanine aminotransferase increased 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Aspartate aminotransferase increased 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Metabolism and nutrition disorders
    Failure to thrive 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Hyperglycaemia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Hyponatraemia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Insulin resistance 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Dehydration 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Bone pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Intervertebral disc protrusion 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Muscular weakness 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Pain in extremity 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression 0/6 (0%) 4/18 (22.2%) 1/18 (5.6%) 1/32 (3.1%) 5/48 (10.4%) 0/15 (0%)
    Pericardial effusion malignant 0/6 (0%) 0/18 (0%) 0/18 (0%) 3/32 (9.4%) 1/48 (2.1%) 0/15 (0%)
    Metastases to central nervous system 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Cancer pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Intracranial tumour haemorrhage 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Malignant ascites 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Metastatic malignant melanoma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Basal cell carcinoma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Chronic myeloid leukaemia recurrent 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Malignant pleural effusion 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Metastases to meninges 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Penile squamous cell carcinoma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Nervous system disorders
    Seizure 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Syncope 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Central nervous system haemorrhage 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Cerebral haemorrhage 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Cognitive disorder 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Embolic stroke 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Haemorrhage intracranial 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Haemorrhagic stroke 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Headache 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Ischaemic stroke 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Nervous system disorder 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Transient ischaemic attack 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Ataxia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Central nervous system lesion 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Cerebral ischaemia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Dysarthria 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Hydrocephalus 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Presyncope 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Status epilepticus 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Psychiatric disorders
    Mental status changes 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Confusional state 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 3/48 (6.3%) 0/15 (0%)
    Suicidal ideation 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 2/48 (4.2%) 4/15 (26.7%)
    Hypoxia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 2/15 (13.3%)
    Pulmonary embolism 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Pneumonitis 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 2/48 (4.2%) 0/15 (0%)
    Cough 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 2/15 (13.3%)
    Pleural effusion 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Respiratory failure 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Acute respiratory distress syndrome 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Haemoptysis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Pneumothorax 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Dyspnoea exertional 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Pleuritic pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Skin and subcutaneous tissue disorders
    Eczema 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Rash maculo-papular 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Vascular disorders
    Haematoma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Other (Not Including 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 17/18 (94.4%) 17/18 (94.4%) 31/32 (96.9%) 45/48 (93.8%) 15/15 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/6 (0%) 1/18 (5.6%) 3/18 (16.7%) 5/32 (15.6%) 4/48 (8.3%) 3/15 (20%)
    Increased tendency to bruise 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 1/15 (6.7%)
    Cardiac disorders
    Sinus tachycardia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 0/15 (0%)
    Palpitations 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Sinus bradycardia 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Atrial fibrillation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Atrial flutter 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cardiac failure congestive 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Ear and labyrinth disorders
    Tinnitus 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 1/15 (6.7%)
    Deafness unilateral 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vertigo 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Ear discomfort 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Ear pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Endocrine disorders
    Hypothyroidism 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 3/32 (9.4%) 2/48 (4.2%) 0/15 (0%)
    Hyperthyroidism 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Eye disorders
    Vision blurred 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 6/32 (18.8%) 5/48 (10.4%) 0/15 (0%)
    Dry eye 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Visual impairment 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 1/15 (6.7%)
    Blepharospasm 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Lacrimation increased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Photopsia 1/6 (16.7%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vitreous floaters 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Asthenopia 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Cataract 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Eye pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Eyelid margin crusting 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Eyelid oedema 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Dyschromatopsia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Eye swelling 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cataract cortical 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Gastrointestinal disorders
    Nausea 3/6 (50%) 8/18 (44.4%) 9/18 (50%) 16/32 (50%) 33/48 (68.8%) 8/15 (53.3%)
    Diarrhoea 1/6 (16.7%) 8/18 (44.4%) 7/18 (38.9%) 17/32 (53.1%) 21/48 (43.8%) 8/15 (53.3%)
    Constipation 1/6 (16.7%) 6/18 (33.3%) 5/18 (27.8%) 9/32 (28.1%) 8/48 (16.7%) 4/15 (26.7%)
    Vomiting 1/6 (16.7%) 1/18 (5.6%) 5/18 (27.8%) 9/32 (28.1%) 19/48 (39.6%) 5/15 (33.3%)
    Abdominal pain 3/6 (50%) 1/18 (5.6%) 2/18 (11.1%) 6/32 (18.8%) 5/48 (10.4%) 2/15 (13.3%)
    Dry mouth 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 5/32 (15.6%) 2/48 (4.2%) 2/15 (13.3%)
    Abdominal distension 0/6 (0%) 4/18 (22.2%) 1/18 (5.6%) 1/32 (3.1%) 4/48 (8.3%) 0/15 (0%)
    Abdominal discomfort 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 2/32 (6.3%) 5/48 (10.4%) 0/15 (0%)
    Gastrooesophageal reflux disease 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 3/48 (6.3%) 3/15 (20%)
    Dyspepsia 0/6 (0%) 4/18 (22.2%) 1/18 (5.6%) 2/32 (6.3%) 1/48 (2.1%) 1/15 (6.7%)
    Dysphagia 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 2/32 (6.3%) 2/48 (4.2%) 3/15 (20%)
    Aphthous ulcer 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 0/15 (0%)
    Flatulence 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Stomatitis 0/6 (0%) 2/18 (11.1%) 2/18 (11.1%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cheilitis 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Mouth ulceration 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Abdominal rigidity 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Abdominal pain upper 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 3/32 (9.4%) 6/48 (12.5%) 0/15 (0%)
    Lip dry 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Lip swelling 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Oesophageal irritation 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Oesophageal pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Toothache 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Hypoaesthesia oral 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Hyperaesthesia teeth 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 1/15 (6.7%)
    Abdominal pain lower 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Eructation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Haemorrhoids 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Abnormal faeces 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Enterocolitis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Haematochezia 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    General disorders
    Fatigue 2/6 (33.3%) 9/18 (50%) 9/18 (50%) 16/32 (50%) 19/48 (39.6%) 12/15 (80%)
    Oedema peripheral 1/6 (16.7%) 1/18 (5.6%) 4/18 (22.2%) 6/32 (18.8%) 5/48 (10.4%) 4/15 (26.7%)
    Pyrexia 0/6 (0%) 3/18 (16.7%) 2/18 (11.1%) 6/32 (18.8%) 7/48 (14.6%) 2/15 (13.3%)
    Pain 0/6 (0%) 3/18 (16.7%) 2/18 (11.1%) 4/32 (12.5%) 3/48 (6.3%) 1/15 (6.7%)
    Chest discomfort 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 3/32 (9.4%) 5/48 (10.4%) 2/15 (13.3%)
    Non-cardiac chest pain 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 1/32 (3.1%) 3/48 (6.3%) 3/15 (20%)
    Influenza like illness 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 4/32 (12.5%) 3/48 (6.3%) 1/15 (6.7%)
    Asthenia 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 5/48 (10.4%) 1/15 (6.7%)
    Chills 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 3/32 (9.4%) 2/48 (4.2%) 2/15 (13.3%)
    Gait disturbance 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 4/48 (8.3%) 0/15 (0%)
    Peripheral swelling 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Chest pain 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 0/15 (0%)
    Thirst 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Axillary pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Exercise tolerance decreased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Feeling abnormal 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Feeling jittery 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Swelling face 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 1/15 (6.7%)
    Mucosal inflammation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Swelling 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Temperature intolerance 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Immune system disorders
    Seasonal allergy 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 3/48 (6.3%) 0/15 (0%)
    Contrast media allergy 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Infections and infestations
    Upper respiratory tract infection 1/6 (16.7%) 0/18 (0%) 3/18 (16.7%) 12/32 (37.5%) 7/48 (14.6%) 3/15 (20%)
    Nasopharyngitis 0/6 (0%) 1/18 (5.6%) 4/18 (22.2%) 5/32 (15.6%) 7/48 (14.6%) 1/15 (6.7%)
    Urinary tract infection 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 6/32 (18.8%) 9/48 (18.8%) 1/15 (6.7%)
    Sinusitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 4/32 (12.5%) 3/48 (6.3%) 4/15 (26.7%)
    Pneumonia 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 2/32 (6.3%) 1/48 (2.1%) 2/15 (13.3%)
    Bronchitis 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 3/32 (9.4%) 0/48 (0%) 2/15 (13.3%)
    Influenza 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Oral candidiasis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 1/15 (6.7%)
    Viral infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Vulvovaginal mycotic infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Conjunctivitis viral 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Diarrhoea infectious 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Folliculitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 2/15 (13.3%)
    Fungal skin infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Infectious pleural effusion 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Laryngitis viral 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Nail infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Nasal herpes 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Onychomycosis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Otitis externa 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Paronychia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Skin candida 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vaginal infection 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cellulitis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 0/15 (0%)
    Gastroenteritis viral 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 2/32 (6.3%) 0/48 (0%) 1/15 (6.7%)
    Rhinitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Ear infection bacterial 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Kidney infection 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Oral herpes 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vulvovaginal candidiasis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Herpes zoster 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Injury, poisoning and procedural complications
    Skin Laceration 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Rib fracture 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Procedural pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Radiation neuropathy 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Radiation pneumonitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Fall 0/6 (0%) 0/18 (0%) 0/18 (0%) 4/32 (12.5%) 2/48 (4.2%) 1/15 (6.7%)
    Arthropod bite 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Corneal abrasion 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Foot fracture 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Joint dislocation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Investigations
    Amylase increased 0/6 (0%) 5/18 (27.8%) 5/18 (27.8%) 10/32 (31.3%) 9/48 (18.8%) 3/15 (20%)
    Lipase increased 0/6 (0%) 5/18 (27.8%) 4/18 (22.2%) 12/32 (37.5%) 6/48 (12.5%) 3/15 (20%)
    Aspartate aminotransferase increased 0/6 (0%) 3/18 (16.7%) 7/18 (38.9%) 10/32 (31.3%) 9/48 (18.8%) 2/15 (13.3%)
    Alanine aminotransferase increased 0/6 (0%) 3/18 (16.7%) 3/18 (16.7%) 6/32 (18.8%) 5/48 (10.4%) 1/15 (6.7%)
    Blood insulin increased 0/6 (0%) 4/18 (22.2%) 2/18 (11.1%) 4/32 (12.5%) 5/48 (10.4%) 0/15 (0%)
    Weight decreased 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 5/32 (15.6%) 6/48 (12.5%) 2/15 (13.3%)
    Blood creatine phosphokinase increased 0/6 (0%) 2/18 (11.1%) 2/18 (11.1%) 4/32 (12.5%) 4/48 (8.3%) 1/15 (6.7%)
    Lymphocyte count decreased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 1/15 (6.7%)
    Weight increased 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 1/32 (3.1%) 4/48 (8.3%) 1/15 (6.7%)
    Blood alkaline phosphatase increased 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Blood testosterone decreased 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 4/48 (8.3%) 1/15 (6.7%)
    Blood thyroid stimulating hormone decreased 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Blood bilirubin increased 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Blood lactate dehydrogenase increased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 1/15 (6.7%)
    Blood thyroid stimulating hormone increased 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 3/48 (6.3%) 0/15 (0%)
    Activated partial thromboplastin time prolonged 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Electrocardiogram QT prolonged 2/6 (33.3%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Bacterial test positive 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Ejection fraction decreased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Heart rate increased 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Urinary sediment present 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Urine leukocyte esterase positive 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    White blood cells urine positive 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Blood creatinine increased 0/6 (0%) 2/18 (11.1%) 2/18 (11.1%) 4/32 (12.5%) 3/48 (6.3%) 1/15 (6.7%)
    Blood alkaline phosphatase decreased 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Blood magnesium decreased 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Blood phosphorus decreased 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Blood sodium increased 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Electrocardiogram T wave abnormal 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Haematocrit decreased 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Haemoglobin decreased 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    White blood cell count increased. 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/6 (0%) 5/18 (27.8%) 1/18 (5.6%) 10/32 (31.3%) 12/48 (25%) 5/15 (33.3%)
    Hypophosphataemia 0/6 (0%) 0/18 (0%) 2/18 (11.1%) 7/32 (21.9%) 4/48 (8.3%) 1/15 (6.7%)
    Hypomagnesaemia 0/6 (0%) 0/18 (0%) 3/18 (16.7%) 4/32 (12.5%) 2/48 (4.2%) 3/15 (20%)
    Hypokalaemia 0/6 (0%) 3/18 (16.7%) 1/18 (5.6%) 5/32 (15.6%) 5/48 (10.4%) 3/15 (20%)
    Hyponatraemia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 4/32 (12.5%) 3/48 (6.3%) 1/15 (6.7%)
    Dehydration 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Hyperglycaemia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Increased appetite 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Hyperlipidaemia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Hypoalbuminaemia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 0/15 (0%)
    Gout 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Hyperuricaemia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Musculoskeletal and connective tissue disorders
    Muscle spasms 1/6 (16.7%) 1/18 (5.6%) 4/18 (22.2%) 8/32 (25%) 13/48 (27.1%) 3/15 (20%)
    Back pain 1/6 (16.7%) 3/18 (16.7%) 5/18 (27.8%) 11/32 (34.4%) 10/48 (20.8%) 1/15 (6.7%)
    Musculoskeletal pain 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 3/32 (9.4%) 8/48 (16.7%) 3/15 (20%)
    Arthralgia 1/6 (16.7%) 4/18 (22.2%) 1/18 (5.6%) 10/32 (31.3%) 10/48 (20.8%) 0/15 (0%)
    Pain in extremity 1/6 (16.7%) 3/18 (16.7%) 3/18 (16.7%) 2/32 (6.3%) 3/48 (6.3%) 2/15 (13.3%)
    Musculoskeletal chest pain 2/6 (33.3%) 1/18 (5.6%) 1/18 (5.6%) 4/32 (12.5%) 3/48 (6.3%) 1/15 (6.7%)
    Joint swelling 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 5/32 (15.6%) 2/48 (4.2%) 0/15 (0%)
    Myalgia 0/6 (0%) 4/18 (22.2%) 1/18 (5.6%) 6/32 (18.8%) 3/48 (6.3%) 1/15 (6.7%)
    Bone pain 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 6/48 (12.5%) 0/15 (0%)
    Musculoskeletal discomfort 0/6 (0%) 0/18 (0%) 2/18 (11.1%) 3/32 (9.4%) 2/48 (4.2%) 0/15 (0%)
    Flank pain 0/6 (0%) 2/18 (11.1%) 2/18 (11.1%) 3/32 (9.4%) 0/48 (0%) 0/15 (0%)
    Muscular weakness 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 5/32 (15.6%) 1/48 (2.1%) 0/15 (0%)
    Pain in jaw 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 2/15 (13.3%)
    Arthritis 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Fracture pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Limb discomfort 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Musculoskeletal stiffness 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Groin pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Neck pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 2/15 (13.3%)
    Osteopenia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Bursitis 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Tendonitis 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pericardial effusion malignant 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 1/15 (6.7%)
    Melanocytic naevus 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Skin papilloma 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Tumour pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Basal cell carcinoma 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Dysplastic naevus 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Squamous cell carcinoma 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Nervous system disorders
    Headache 0/6 (0%) 8/18 (44.4%) 7/18 (38.9%) 14/32 (43.8%) 18/48 (37.5%) 6/15 (40%)
    Dizziness 0/6 (0%) 5/18 (27.8%) 1/18 (5.6%) 5/32 (15.6%) 3/48 (6.3%) 1/15 (6.7%)
    Peripheral sensory neuropathy 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 6/32 (18.8%) 3/48 (6.3%) 0/15 (0%)
    Paraesthesia 1/6 (16.7%) 2/18 (11.1%) 1/18 (5.6%) 2/32 (6.3%) 3/48 (6.3%) 1/15 (6.7%)
    Dysgeusia 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 3/48 (6.3%) 1/15 (6.7%)
    Tremor 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 3/32 (9.4%) 3/48 (6.3%) 1/15 (6.7%)
    Amnesia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 3/48 (6.3%) 0/15 (0%)
    Balance disorder 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 2/32 (6.3%) 5/48 (10.4%) 0/15 (0%)
    Hypoaesthesia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 4/48 (8.3%) 1/15 (6.7%)
    Visual field defect 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 5/48 (10.4%) 1/15 (6.7%)
    Seizure 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 1/48 (2.1%) 2/15 (13.3%)
    Aphasia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 3/48 (6.3%) 1/15 (6.7%)
    Disturbance in attention 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Dysarthria 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Memory impairment 1/6 (16.7%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 0/15 (0%)
    Sinus headache 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Somnolence 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Syncope 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 1/15 (6.7%)
    Burning sensation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Cognitive disorder 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Neuralgia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Parosmia 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Peripheral motor neuropathy 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Taste disorder 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 1/32 (3.1%) 1/48 (2.1%) 1/15 (6.7%)
    Neuropathy peripheral 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Presyncope 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Dizziness postural 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Psychiatric disorders
    Insomnia 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 6/32 (18.8%) 6/48 (12.5%) 3/15 (20%)
    Anxiety 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 5/32 (15.6%) 2/48 (4.2%) 1/15 (6.7%)
    Depression 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 4/32 (12.5%) 3/48 (6.3%) 0/15 (0%)
    Bruxism 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Anticipatory anxiety 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Confusional state 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 1/48 (2.1%) 0/15 (0%)
    Disorientation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Nervousness 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Stress 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Renal and urinary disorders
    Pollakiuria 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 2/32 (6.3%) 4/48 (8.3%) 0/15 (0%)
    Proteinuria 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 2/15 (13.3%)
    Haematuria 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Dysuria 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Renal failure 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Urinary retention 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Urinary tract pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Reproductive system and breast disorders
    Vulvovaginal dryness 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Nipple pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Metrorrhagia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Breast pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/6 (16.7%) 7/18 (38.9%) 6/18 (33.3%) 13/32 (40.6%) 14/48 (29.2%) 8/15 (53.3%)
    Dyspnoea 0/6 (0%) 4/18 (22.2%) 5/18 (27.8%) 7/32 (21.9%) 10/48 (20.8%) 4/15 (26.7%)
    Dyspnoea exertional 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 1/32 (3.1%) 4/48 (8.3%) 1/15 (6.7%)
    Oropharyngeal pain 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 5/32 (15.6%) 5/48 (10.4%) 2/15 (13.3%)
    Epistaxis 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 1/32 (3.1%) 4/48 (8.3%) 2/15 (13.3%)
    Productive cough 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 4/32 (12.5%) 5/48 (10.4%) 0/15 (0%)
    Nasal congestion 0/6 (0%) 2/18 (11.1%) 3/18 (16.7%) 0/32 (0%) 0/48 (0%) 3/15 (20%)
    Haemoptysis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 1/15 (6.7%)
    Hypoxia 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 2/48 (4.2%) 2/15 (13.3%)
    Rhinorrhoea 1/6 (16.7%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 2/48 (4.2%) 0/15 (0%)
    Sinus congestion 1/6 (16.7%) 1/18 (5.6%) 0/18 (0%) 4/32 (12.5%) 1/48 (2.1%) 0/15 (0%)
    Dysphonia 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 3/48 (6.3%) 1/15 (6.7%)
    Rhinitis allergic 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Sputum discoloured 0/6 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Dry throat 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Hiccups 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Laryngeal inflammation 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Pleural effusion 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Pleuritic pain 0/6 (0%) 0/18 (0%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 1/15 (6.7%)
    Throat irritation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Wheezing 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 2/15 (13.3%)
    Nasal dryness 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Pleurisy 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Pneumothorax 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Pulmonary hypertension 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Respiratory tract irritation 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Sneezing 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 1/15 (6.7%)
    Upper-airway cough syndrome 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Skin and subcutaneous tissue disorders
    Rash 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 3/32 (9.4%) 3/48 (6.3%) 0/15 (0%)
    Photosensitivity reaction 0/6 (0%) 0/18 (0%) 4/18 (22.2%) 3/32 (9.4%) 5/48 (10.4%) 0/15 (0%)
    Pruritus 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 7/32 (21.9%) 3/48 (6.3%) 0/15 (0%)
    Dry skin 0/6 (0%) 1/18 (5.6%) 2/18 (11.1%) 4/32 (12.5%) 3/48 (6.3%) 0/15 (0%)
    Night sweats 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 0/32 (0%) 4/48 (8.3%) 0/15 (0%)
    Dermatitis acneiform 0/6 (0%) 2/18 (11.1%) 1/18 (5.6%) 3/32 (9.4%) 1/48 (2.1%) 0/15 (0%)
    Alopecia 0/6 (0%) 2/18 (11.1%) 0/18 (0%) 0/32 (0%) 5/48 (10.4%) 1/15 (6.7%)
    Hyperhidrosis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 3/48 (6.3%) 1/15 (6.7%)
    Onychoclasis 0/6 (0%) 3/18 (16.7%) 0/18 (0%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Rash pruritic 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 3/32 (9.4%) 1/48 (2.1%) 0/15 (0%)
    Dermatitis contact 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 2/48 (4.2%) 0/15 (0%)
    Eczema 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Erythema 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)
    Pain of skin 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 0/15 (0%)
    Skin disorder 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 0/15 (0%)
    Dermal cyst 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Dermatitis 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Dermatitis atopic 0/6 (0%) 0/18 (0%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Nail disorder 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Petechiae 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Skin hyperpigmentation 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Urticaria 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 1/48 (2.1%) 1/15 (6.7%)
    Nail growth abnormal 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Rash erythematous 0/6 (0%) 2/18 (11.1%) 2/18 (11.1%) 0/32 (0%) 4/48 (8.3%) 0/15 (0%)
    Rash maculo-papular 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 1/32 (3.1%) 1/48 (2.1%) 1/15 (6.7%)
    Actinic keratosis 0/6 (0%) 0/18 (0%) 1/18 (5.6%) 1/32 (3.1%) 0/48 (0%) 0/15 (0%)
    Rash papular 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 0/15 (0%)
    Eczema nummular 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Ingrowing nail 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vascular disorders
    Hypertension 0/6 (0%) 2/18 (11.1%) 6/18 (33.3%) 11/32 (34.4%) 10/48 (20.8%) 1/15 (6.7%)
    Hypotension 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 2/32 (6.3%) 0/48 (0%) 2/15 (13.3%)
    Deep vein thrombosis 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Vascular pain 0/6 (0%) 1/18 (5.6%) 0/18 (0%) 0/32 (0%) 0/48 (0%) 0/15 (0%)
    Hot flush 0/6 (0%) 0/18 (0%) 0/18 (0%) 2/32 (6.3%) 2/48 (4.2%) 0/15 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    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

    Name/Title Medical Director
    Organization Takeda
    Phone +1-877-825-3327
    Email trialdisclosures@takeda.com
    Responsible Party:
    Ariad Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01449461
    Other Study ID Numbers:
    • AP26113-11-101
    • 2011-005718-12
    • U1111-1196-8197
    First Posted:
    Oct 10, 2011
    Last Update Posted:
    Aug 17, 2021
    Last Verified:
    Jul 1, 2021