ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants

Sponsor
Ariad Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02737501
Collaborator
(none)
275
91
3
56.1
3
0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic non-small cell lung cancer (NSCLC) participants naive to ALK inhibitors, as evidenced by progression-free survival (PFS).

Detailed Description

The purpose of this phase III, randomized, open-label, comparative, multicenter, international study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC participants who have not previously been treated with an ALK inhibitor. Participants will be stratified by the presence of CNS metastases at baseline and prior chemotherapy used for locally advanced or metastatic disease. Participants will be randomized in a 1:1 ratio to receive either brigatinib, 90 mg orally once daily (QD) for 7 days, then a 180 mg orally QD, or crizotinib, 250 mg orally twice daily (BID). Participants will receive treatment until disease progression, intolerable toxicity, consent withdrawal, or death. Crossover from crizotinib to brigatinib is also permitted.

The total estimated duration of the study is at least 4.5 years, including 1.5 years to accrue participants, with at least 3 years for treatment and follow-up.

Study Design

Study Type:
Interventional
Actual Enrollment :
275 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) Versus Crizotinib in Patients With ALK-positive Advanced Lung Cancer
Actual Study Start Date :
May 26, 2016
Actual Primary Completion Date :
Jul 28, 2020
Actual Study Completion Date :
Jan 29, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Randomized Phase: Brigatinib 90 mg QD/180 QD

Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).

Drug: Brigatinib
Brigatinib tablets

Active Comparator: Randomized Phase: Crizotinib 250 mg BID

Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).

Drug: Crizotinib
Crizotinib tablets
Other Names:
  • Xalkori
  • Experimental: Crossover Phase: Brigatinib 90 mg QD/180 mg QD

    Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).

    Drug: Brigatinib
    Brigatinib tablets

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival (PFS) [Up to end of study (Up to 56 months)]

      PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event.

    Secondary Outcome Measures

    1. Confirmed Objective Response Rate (ORR) [Baseline up to end of treatment (Up to 36 months)]

      ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters.

    2. Confirmed Intracranial ORR (iORR) [Baseline up to end of treatment (Up to 36 months)]

      ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

    3. Intracranial Progression Free Survival [Baseline up to end of study (Up to 56 months)]

      Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

    4. Overall Survival (OS) [Baseline up to end of study (Up to 56 months)]

      Overall survival is defined as the time from randomization until death due to any cause.

    5. Duration of Response (DOR) [Baseline up to end of study (Up to 56 months)]

      Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target lesions, taking as reference the baseline sum diameters. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and for non-target lesions, unequivocal progression of existing non-target lesions.

    6. Time to Response (TTR) [Baseline up to end of treatment (Up to 36 months)]

      Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

    7. Disease Control Rate (DCR) [Baseline up to end of treatment (Up to 36 months)]

      Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: SLD increased by at least 20% from the smallest value on study, SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

    8. Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)]

      An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the last dose of the treatment to which the participant was assigned, or the day before start of brigatinib therapy in crossover participant.

    9. Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) [Baseline and Month 36]

      HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. The 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into overall score ranging from 0 to 100, where lower scores indicate better QOL. A negative change from Baseline indicates improvement.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Have histologically or cytologically confirmed stage IIIB (and not a candidate for definitive multimodality therapy) or stage four (IV) NSCLC.

    2. Must have documented ALK rearrangement.

    3. Have sufficient tumor tissue available for central analysis.

    4. Have at least 1 measurable (that is, target) lesion per RECIST v1.1.

    5. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (of the United States) (NCI) Common Terminology Criteria for Adverse Events (version 4.0) (CTCAE v 4.0) grade be less than or equal to (<=) 1.

    6. Are a male or female participants greater than or equal to (>=)18 years old.

    7. Have adequate organ function, as defined by the study protocol.

    8. Have Eastern Cooperative Oncology Group (ECOG) performance status <=2.

    9. Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of <= 450 millisecond (msec) in males or <=470 msec in females.

    10. For female participants of childbearing potential, have a negative pregnancy test documented prior to randomization.

    11. For female and male participants who are fertile, agree to use a highly effective form of contraception, as defined by the study protocol.

    12. Provide signed and dated informed consent indicating that the participants has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating.

    13. Have the willingness and ability to comply with scheduled visit and study procedures.

    Exclusion Criteria:
    1. Previously received an investigational antineoplastic agent for NSCLC.

    2. Previously received any prior tyrosine kinase inhibitor (TKI), including ALK-targeted TKIs.

    3. Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease.

    4. Received chemotherapy or radiation within 14 days of first dose of study drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT).

    5. Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug.

    6. Had major surgery within 30 days of the first dose of study drug, minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.

    7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or participants with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.

    8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization.

    9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.

    10. Be pregnant, planning a pregnancy, or breastfeeding.

    11. Have significant, uncontrolled, or active cardiovascular disease, as defined by the study protocol.

    12. Have uncontrolled hypertension.

    13. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.

    14. Have an ongoing or active infection.

    15. Have a known history of human immunodeficiency virus (HIV) infection.

    16. Have a known or suspected hypersensitivity to brigatinib or its excipients and/or crizotinib or its excipients.

    17. Have malabsorption syndrome or other gastrointestinal (GI) illness or condition.

    18. Have any condition or illness that, in the opinion of the investigator, would compromise participant's safety or interfere with the evaluation of the study drug.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 USOR - Arizona Oncology Associates - Sedona Sedona Arizona United States 86336
    2 Kaiser Permanente Bellflower Medical Offices Bellflower California United States 90706
    3 University of Colorado Cancer Center Aurora Colorado United States 80045
    4 Rocky Mountain Cancer Centers - Boulder Boulder Colorado United States 80303-1385
    5 Sylvester Comprehensive Cancer Center Deerfield Beach Florida United States 33442
    6 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    7 West Michigan Cancer Center Kalamazoo Michigan United States 49007
    8 Minnesota Oncology Coon Rapids Minnesota United States 55433
    9 Montefiore Medical Center Bronx New York United States 10461
    10 Oncology Hematology Care - Blue Ash Cincinnati Ohio United States 45242-5665
    11 Stephenson Cancer Center Oklahoma City Oklahoma United States 73104
    12 Virginia Cancer Specialists - Fairfax Office Fairfax Virginia United States 22031
    13 Saint George Hospital Kogarah New South Wales Australia 2217
    14 Royal North Shore Hospital St Leonards New South Wales Australia 2065
    15 Monash Medical Centre Bentleigh East Victoria Australia 3165
    16 Saint Vincent's Hospital Melbourne Fitzroy Victoria Australia 3065
    17 Universitatsklinium St. Polten Sankt Polten Lower Austria Austria 3100
    18 Otto-Wagner-Spital Baumgartner Hohe Vienna Austria 1140
    19 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
    20 Odense University Hospital Odense C Denmark 5000
    21 Centre de Lutte Contre le Cancer Francois Baclesse CAEN Cedex 5 Basse-normandie France 14076
    22 Hopital Charles Nicolle Rouen Haute-normandie France 76041
    23 Centre Hospitalier Intercommunal de Creteil Creteil Ile-de-france France 94010
    24 Hopital Tenon Paris Ile-de-france France 75020
    25 Centre Hospitalier Universitaire Hopital Nord Marseille Cedex 20 Provence Alpes COTE D'azur France 13915
    26 Hopital Albert Michallon Grenoble Cedex 9 Rhone-alpes France 38043
    27 Centre Leon Berard Lyon Rhone-alpes France 69008
    28 Universitatsklinik Freiburg Freiburg Baden-wuerttemberg Germany 79106
    29 Thoraxklinik Heidelberg gGmbH Heidelberg Baden-wuerttemberg Germany 69126
    30 Pius Hospital Oldenburg Oldenburg Niedersachsen Germany 26121
    31 Kliniken der Stadt Koeln gGmbH - Krankenhaus Merheim Koln Nordrhein-westfalen Germany 51109
    32 Evangelische Lungenklinik Berlin Berlin Germany 13125
    33 Studiengesellschaft Haemato-Onkologie Hamburg Prof. Laack und Partner Hamburg Germany 20251
    34 Tuen Mun Hospital Tuen Mun New Territories Hong Kong
    35 Queen Mary Hospital Hong Kong Hong Kong
    36 Queen Elizabeth Hospital Kowloon Hong Kong 150001
    37 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola Forli-cesena Italy 47014
    38 Azienda Ospedaliera San Gerardo di Monza Monza Monza E Brianza Italy 20052
    39 Centro di Riferimento Oncologico di Aviano Aviano Pordenone Italy 33081
    40 Azienda Ospedaliera San Giuseppe Moscati Avellino Italy 83100
    41 Istituto Oncologico di Bari Giovanni Paolo II Bari Italy 70124
    42 Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi Bologna Italy 40138
    43 Istituto Scientifico Universitario San Raffaele Milano Italy 20132
    44 Istituto Europeo di Oncologia Milano Italy 20141
    45 Istituto Tumori Napoli Fondazione G. Pascale Napoli Italy 80131
    46 Azienda Ospedaliero Universitaria Maggiore della Carita Novara Italy 28100
    47 Azienda Ospedaliera di Perugia - Ospedale S. Maria della Misericordia Perugia Italy 06132
    48 Azienda Unita Sanitaria Locale di Ravenna Ravenna Italy 48121
    49 Policlinico Universitario Campus Bio-Medico Roma Italy 00128
    50 Chungbuk National University Hospital Cheongju Chungcheongbuk-do Korea, Republic of 28644
    51 National Cancer Center Goyang-si Gyeonggi-do Korea, Republic of 10408
    52 Seoul National University Bundang Hospital Seongnam-si Gyeonggi-do Korea, Republic of 13620
    53 Seoul National University Hospital Seoul Korea, Republic of 03080
    54 Severance Hospital Seoul Korea, Republic of 03722
    55 Asan Medical Center Seoul Korea, Republic of 05505
    56 Samsung Medical Center Seoul Korea, Republic of 06351
    57 The Catholic University of Korea Seoul Korea, Republic of 06591
    58 Centre Hospitalier de Luxembourg - Hopital Municipal Luxembourg Luxembourg 1210
    59 Amphia Ziekenhuis - Locatie Langendijk Breda Breda Noord-brabant Netherlands 4818 CK
    60 Antoni van Leeuwenhoekziekenhuis Amsterdam Noord-holland Netherlands 1066 CX
    61 Isala Klinieken Zwolle Overijssel Netherlands 8025 AB
    62 Universitair Medisch Centrum Groningen Groningen Netherlands 9713 GZ
    63 Radiumhospitalet Oslo Norway 0379
    64 National University Hospital Singapore Singapore 119228
    65 National Cancer Centre Singapore Singapore Singapore 169610
    66 OncoCare Cancer Centre Singapore Singapore 258499
    67 Hospital Universitario Central de Asturias Oviedo Asturias Spain 33011
    68 Hospital Universitari Germans Trias i Pujol Badalona Barcelona Spain 08916
    69 Hospital Universitario Puerta de Hierro - Majadahonda Majadahonda Madrid Spain 28222
    70 Hospital General Universitario de Alicante Alicante Spain 03010
    71 Hospital Universitario Vall d'Hebron Barcelona Spain 08035
    72 Hospital Teresa Herrera - Materno Infantil La Coruna Spain 15006
    73 Hospital Ramon Y Cajal Madrid Spain 28034
    74 Hospital Universitario La Paz Madrid Spain 28046
    75 Hospital Regional Universitario Carlos Haya Malaga Instituto de Neurociencias Clinicas Malaga Spain 29010
    76 Hospital Universitario Marques de Valdecilla Santander Spain 39008
    77 Hospital Universitario Virgen del Rocio Sevilla Spain 41013
    78 Hospital Clinico Universitario de Valencia Valencia Spain 46010
    79 Karolinska Universitetssjukhuset Stockholm Sweden 171 76
    80 University Hospital Zurich Zurich Switzerland 8091
    81 National Cheng Kung University Tainan Taipei Taiwan 70403
    82 China Medical University Hospital Taichung Taiwan 404
    83 Taichung Veterans General Hospital Taichung Taiwan 40705
    84 National Taiwan University Hospital Taipei Taiwan 100
    85 Taipei Veterans General Hospital Taipei Taiwan 11217
    86 Leicester Royal Infirmary Leicester England United Kingdom LE1 5WW
    87 University College London London England United Kingdom NW1 2PG
    88 Guy's and Saint Thomas' NHS Foundation Trust London England United Kingdom SE1 9RT
    89 Royal Marsden NHS Trust London England United Kingdom SW3 6JJ
    90 Maidstone Hospital Maidstone England United Kingdom ME16 9QQ
    91 The Christie NHS Foundation Trust Manchester England United Kingdom M20 4BX

    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:
    NCT02737501
    Other Study ID Numbers:
    • AP26113-13-301
    • U1111-1210-4363
    • 2015-003447-19
    First Posted:
    Apr 14, 2016
    Last Update Posted:
    Aug 20, 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
    Keywords provided by Ariad Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 92 investigative sites in Australia, Hong Kong, Singapore, South Korea, Taiwan, Austria, Denmark, France, Germany, Italy, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom, Canada, and the United States of America from 26 May 2016 to 29 January 2021.
    Pre-assignment Detail Participants with anaplastic lymphoma kinase and non-small-cell lung cancer (ALK+ NSCLC) who had not previously received an ALK-targeted tyrosine kinase inhibitor (TKI) were enrolled in 1:1 ratio to receive brigatinib 90 mg for 7 days followed by 180 mg or crizotinib 250 mg. Participants from crizotinib arm who experienced progressive disease (PD) or received radiotherapy to the brain in Randomized Phase were crossed over to receive brigatinib 90 mg/180 mg in the Crossover Phase.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, once daily (QD) for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until disease progression (PD), intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, twice daily (BID) in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the blinded Independent Review Committee (BIRC) or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Period Title: Randomized Phase
    STARTED 137 138 0
    Safety Analysis Set 136 137 0
    COMPLETED 20 84 0
    NOT COMPLETED 117 54 0
    Period Title: Randomized Phase
    STARTED 0 0 65
    COMPLETED 0 0 10
    NOT COMPLETED 0 0 55

    Baseline Characteristics

    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Total
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Total of all reporting groups
    Overall Participants 137 138 275
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    57.9
    (13.46)
    58.6
    (11.42)
    58.2
    (12.46)
    Sex: Female, Male (Count of Participants)
    Female
    69
    50.4%
    81
    58.7%
    150
    54.5%
    Male
    68
    49.6%
    57
    41.3%
    125
    45.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    59
    43.1%
    49
    35.5%
    108
    39.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    2
    1.4%
    2
    0.7%
    White
    76
    55.5%
    86
    62.3%
    162
    58.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    1.5%
    1
    0.7%
    3
    1.1%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic, Latino or Spanish
    6
    4.4%
    10
    7.2%
    16
    5.8%
    Not Hispanic, Latino or Spanish
    131
    95.6%
    128
    92.8%
    259
    94.2%
    Region of Enrollment (Count of Participants)
    Australia
    2
    1.5%
    5
    3.6%
    7
    2.5%
    Hong Kong
    10
    7.3%
    6
    4.3%
    16
    5.8%
    Singapore
    5
    3.6%
    1
    0.7%
    6
    2.2%
    Korea, Republic Of
    29
    21.2%
    28
    20.3%
    57
    20.7%
    Taiwan, Province Of China
    12
    8.8%
    9
    6.5%
    21
    7.6%
    Austria
    5
    3.6%
    4
    2.9%
    9
    3.3%
    Denmark
    2
    1.5%
    1
    0.7%
    3
    1.1%
    France
    7
    5.1%
    4
    2.9%
    11
    4%
    Germany
    6
    4.4%
    11
    8%
    17
    6.2%
    Italy
    19
    13.9%
    19
    13.8%
    38
    13.8%
    Luxembourg
    1
    0.7%
    0
    0%
    1
    0.4%
    Netherlands
    5
    3.6%
    6
    4.3%
    11
    4%
    Norway
    0
    0%
    2
    1.4%
    2
    0.7%
    Spain
    14
    10.2%
    17
    12.3%
    31
    11.3%
    Sweden
    0
    0%
    1
    0.7%
    1
    0.4%
    Switzerland
    0
    0%
    1
    0.7%
    1
    0.4%
    United Kingdom
    10
    7.3%
    8
    5.8%
    18
    6.5%
    Canada
    0
    0%
    2
    1.4%
    2
    0.7%
    United States
    10
    7.3%
    13
    9.4%
    23
    8.4%
    Global Health Status/Quality of Life (QoL) (score on a scale) [Mean (Full Range) ]
    Mean (Full Range) [score on a scale]
    60.432
    59.160
    59.796

    Outcome Measures

    1. Primary Outcome
    Title Progression-free Survival (PFS)
    Description PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event.
    Time Frame Up to end of study (Up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 137 138 65
    Median (95% Confidence Interval) [months]
    24.016
    11.072
    16.821
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments P-values are from a log-rank test stratified by randomization stratification factors (current; presence of intracranial central nervous system (iCNS) metastases at baseline and prior chemotherapy for locally advanced or metastatic disease).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.481
    Confidence Interval (2-Sided) 95%
    0.35 to 0.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments The hazard ratio was obtained using a Cox proportional hazards model with randomization stratification factors (current) as covariates.
    2. Secondary Outcome
    Title Confirmed Objective Response Rate (ORR)
    Description ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters.
    Time Frame Baseline up to end of treatment (Up to 36 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 137 138 65
    Number (95% Confidence Interval) [percentage of participants]
    74.5
    54.4%
    62.3
    45.1%
    56.9
    20.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0330
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.74
    Confidence Interval (2-Sided) 95%
    1.04 to 2.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of intracranial central nervous system (iCNS) metastases at Baseline, and prior chemotherapy for locally advanced or metastatic disease (current strata).
    3. Secondary Outcome
    Title Confirmed Intracranial ORR (iORR)
    Description ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.
    Time Frame Baseline up to end of treatment (Up to 36 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 47 49 42
    Number (95% Confidence Interval) [percentage of participants]
    66.0
    48.2%
    14.3
    10.4%
    35.7
    13%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 13.56
    Confidence Interval (2-Sided) 95%
    4.70 to 39.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of prior chemotherapy for Locally advanced or metastatic disease at study entry (current strata).
    4. Secondary Outcome
    Title Intracranial Progression Free Survival
    Description Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.
    Time Frame Baseline up to end of study (Up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 47 49 42
    Median (95% Confidence Interval) [months]
    23.951
    5.520
    24.542
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments P-values are from a log-rank test stratified by randomization stratification factors (current; presence of iCNS metastases at baseline and prior chemotherapy for locally advanced or metastatic disease).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.293
    Confidence Interval (2-Sided) 95%
    0.17 to 0.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments The hazard ratio was obtained using a Cox proportional hazards model with prior chemotherapy for locally advanced or metastatic disease (current strata) as covariate.
    5. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall survival is defined as the time from randomization until death due to any cause.
    Time Frame Baseline up to end of study (Up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 137 138 65
    Median (95% Confidence Interval) [months]
    NA
    NA
    35.023
    6. Secondary Outcome
    Title Duration of Response (DOR)
    Description Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target lesions, taking as reference the baseline sum diameters. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and for non-target lesions, unequivocal progression of existing non-target lesions.
    Time Frame Baseline up to end of study (Up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 102 86 37
    Median (Full Range) [months]
    33.150
    13.832
    19.154
    7. Secondary Outcome
    Title Time to Response (TTR)
    Description Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.
    Time Frame Baseline up to end of treatment (Up to 36 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 137 138 65
    Median (Full Range) [months]
    1.840
    1.873
    1.873
    8. Secondary Outcome
    Title Disease Control Rate (DCR)
    Description Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: SLD increased by at least 20% from the smallest value on study, SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.
    Time Frame Baseline up to end of treatment (Up to 36 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 137 138 65
    Number (95% Confidence Interval) [percentage of participants]
    85.4
    62.3%
    86.2
    62.5%
    73.8
    26.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8220
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    0.47 to 1.82
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of iCNS metastases at Baseline, and prior chemotherapy for locally advanced or metastatic disease (current strata).
    9. Secondary Outcome
    Title Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
    Description An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the last dose of the treatment to which the participant was assigned, or the day before start of brigatinib therapy in crossover participant.
    Time Frame From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)

    Outcome Measure Data

    Analysis Population Description
    Treated Population included all participant who received at least 1 dose of study drug and served as basis of safety analysis.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    Measure Participants 136 137 65
    Number [percentage of participants]
    100
    73%
    100
    72.5%
    98.5
    35.8%
    10. Secondary Outcome
    Title Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0)
    Description HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. The 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into overall score ranging from 0 to 100, where lower scores indicate better QOL. A negative change from Baseline indicates improvement.
    Time Frame Baseline and Month 36

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).
    Measure Participants 104 53
    Mean (Standard Deviation) [score on a scale]
    4.007
    (25.7563)
    -4.088
    (27.4748)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0295
    Comments p-values were obtained using mixed effects models stratified by presence of iCNS metastases at study entry, prior chemotherapy at Baseline.
    Method Mixed Models Analysis
    Comments A mixed effect model is used with an unstructured covariance matrix.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 5.79
    Confidence Interval (2-Sided) 95%
    0.58 to 11.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame All-Cause Mortality - Up to 56 months; Serious and other adverse events - From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)
    Adverse Event Reporting Description All Cause-mortality: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Serious and other (Non-serious): Treated Population included all participants who received ≥1 dose of study drug and served as basis of safety analysis. Crossover Population included participants from 'Crizotinib 250 mg BID' who crossed over to brigatinib following BIRC-assessed PD.
    Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Arm/Group Description Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
    All Cause Mortality
    Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 41/137 (29.9%) 29/138 (21%) 22/65 (33.8%)
    Serious Adverse Events
    Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 56/136 (41.2%) 53/137 (38.7%) 24/65 (36.9%)
    Blood and lymphatic system disorders
    Anaemia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Disseminated Intravascular Coagulation 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Neutropenia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Anaemia Macrocytic 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Cardiac disorders
    Atrial Fibrillation 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Pericardial Effusion 1/136 (0.7%) 2/137 (1.5%) 0/65 (0%)
    Cardiac Tamponade 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Acute Myocardial Infarction 1/136 (0.7%) 0/137 (0%) 1/65 (1.5%)
    Angina Pectoris 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Arrhythmia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Bradycardia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Myocardial Infarction 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Palpitations 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Cardiac Failure 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Ear and labyrinth disorders
    Vertigo Positional 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Gastrointestinal disorders
    Vomiting 2/136 (1.5%) 2/137 (1.5%) 0/65 (0%)
    Diarrhoea 2/136 (1.5%) 1/137 (0.7%) 2/65 (3.1%)
    Nausea 2/136 (1.5%) 1/137 (0.7%) 1/65 (1.5%)
    Constipation 1/136 (0.7%) 0/137 (0%) 1/65 (1.5%)
    Dysphagia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Gastric Haemorrhage 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Inguinal Hernia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Neutropenic Colitis 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Oesophageal Obstruction 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Abdominal Pain Lower 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Abdominal Pain Upper 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Ascites 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Large Intestine Perforation 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Oesophagitis Ulcerative 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Intestinal Obstruction 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Abdominal Pain 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    General disorders
    Pyrexia 4/136 (2.9%) 0/137 (0%) 1/65 (1.5%)
    Asthenia 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Fatigue 1/136 (0.7%) 1/137 (0.7%) 1/65 (1.5%)
    Mucosal Inflammation 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Multiple Organ Dysfunction Syndrome 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Sudden Death 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Non-Cardiac Chest Pain 0/136 (0%) 3/137 (2.2%) 0/65 (0%)
    General Physical Health Deterioration 0/136 (0%) 2/137 (1.5%) 2/65 (3.1%)
    Performance Status Decreased 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Hepatobiliary disorders
    Cholecystitis 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Bile Duct Stone 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Cholestasis 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Hepatocellular Injury 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Drug-Induced Liver Injury 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Infections and infestations
    Pneumonia 6/136 (4.4%) 5/137 (3.6%) 4/65 (6.2%)
    Lower Respiratory Tract Infection 2/136 (1.5%) 0/137 (0%) 1/65 (1.5%)
    Urinary Tract Infection 1/136 (0.7%) 3/137 (2.2%) 0/65 (0%)
    Appendicitis 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Upper Respiratory Tract Infection 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Gastroenteritis 1/136 (0.7%) 0/137 (0%) 1/65 (1.5%)
    Viral Infection 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Respiratory Tract Infection 0/136 (0%) 3/137 (2.2%) 0/65 (0%)
    Cellulitis 0/136 (0%) 2/137 (1.5%) 0/65 (0%)
    Cytomegalovirus Oesophagitis 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Herpes Zoster 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Listeriosis 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Pleural Infection 0/136 (0%) 1/137 (0.7%) 1/65 (1.5%)
    Septic Shock 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Sinusitis Fungal 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Atypical Pneumonia 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Gastroenteritis Viral 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Pyelonephritis Acute 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Covid-19 0/136 (0%) 0/137 (0%) 2/65 (3.1%)
    Salmonella Sepsis 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Injury, poisoning and procedural complications
    Femoral Neck Fracture 2/136 (1.5%) 1/137 (0.7%) 0/65 (0%)
    Fall 1/136 (0.7%) 0/137 (0%) 1/65 (1.5%)
    Ligament Rupture 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Brain Herniation 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Spinal Fracture 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Tibia Fracture 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Toxicity To Various Agents 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Investigations
    Alanine Aminotransferase Increased 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Aspartate Aminotransferase Increased 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    C-Reactive Protein Increased 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Lipase Increased 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Transaminases Abnormal 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Neutrophil Count Decreased 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Platelet Count Decreased 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Metabolism and nutrition disorders
    Hyperkalaemia 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Gout 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Hypoglycaemia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Hyperglycaemia 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Musculoskeletal and connective tissue disorders
    Back Pain 1/136 (0.7%) 2/137 (1.5%) 1/65 (1.5%)
    Muscular Weakness 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Arthritis 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Bone Pain 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Rotator Cuff Syndrome 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm Progression 5/136 (3.7%) 4/137 (2.9%) 3/65 (4.6%)
    Metastases To Meninges 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Malignant Pleural Effusion 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Metastases To Central Nervous System 1/136 (0.7%) 1/137 (0.7%) 1/65 (1.5%)
    Cancer Pain 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Diffuse Large B-Cell Lymphoma 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Invasive Breast Carcinoma 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Lung Adenocarcinoma 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Lung Neoplasm Malignant 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Ovarian Cancer Stage I 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Squamous Cell Carcinoma Of Skin 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Hodgkins Disease 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Tumour Haemorrhage 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Intracranial Tumour Haemorrhage 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Prostate Cancer 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Nervous system disorders
    Headache 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Syncope 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Dizziness 1/136 (0.7%) 2/137 (1.5%) 1/65 (1.5%)
    Seizure 1/136 (0.7%) 1/137 (0.7%) 2/65 (3.1%)
    Balance Disorder 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Cerebrovascular Accident 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Cognitive Disorder 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Dysarthria 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Encephalopathy 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Memory Impairment 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Paraesthesia 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Partial Seizures 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Peripheral Sensory Neuropathy 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Vocal Cord Paralysis 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Ischaemic Stroke 0/136 (0%) 2/137 (1.5%) 0/65 (0%)
    Central Nervous System Lesion 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Aphasia 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Depressed Level Of Consciousness 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Generalised Tonic-Clonic Seizure 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Hemiparesis 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Intraventricular Haemorrhage 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Psychiatric disorders
    Confusional State 2/136 (1.5%) 0/137 (0%) 0/65 (0%)
    Delirium 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Disorientation 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Renal and urinary disorders
    Acute Kidney Injury 1/136 (0.7%) 1/137 (0.7%) 0/65 (0%)
    Urinary Retention 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Haematuria 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Reproductive system and breast disorders
    Menorrhagia 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 3/136 (2.2%) 6/137 (4.4%) 1/65 (1.5%)
    Pulmonary Embolism 3/136 (2.2%) 5/137 (3.6%) 0/65 (0%)
    Pleural Effusion 3/136 (2.2%) 3/137 (2.2%) 1/65 (1.5%)
    Interstitial Lung Disease 3/136 (2.2%) 0/137 (0%) 0/65 (0%)
    Pneumonitis 2/136 (1.5%) 2/137 (1.5%) 2/65 (3.1%)
    Pneumonia Aspiration 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Pneumothorax 1/136 (0.7%) 0/137 (0%) 1/65 (1.5%)
    Pulmonary Oedema 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Respiratory Distress 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Acute Respiratory Failure 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Respiratory Failure 0/136 (0%) 1/137 (0.7%) 0/65 (0%)
    Respiratory Arrest 0/136 (0%) 0/137 (0%) 1/65 (1.5%)
    Skin and subcutaneous tissue disorders
    Rash 1/136 (0.7%) 0/137 (0%) 0/65 (0%)
    Other (Not Including Serious) Adverse Events
    Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 132/136 (97.1%) 135/137 (98.5%) 63/65 (96.9%)
    Blood and lymphatic system disorders
    Anaemia 12/136 (8.8%) 8/137 (5.8%) 5/65 (7.7%)
    Cardiac disorders
    Bradycardia 10/136 (7.4%) 22/137 (16.1%) 0/65 (0%)
    Sinus Bradycardia 7/136 (5.1%) 11/137 (8%) 0/65 (0%)
    Eye disorders
    Vision Blurred 7/136 (5.1%) 14/137 (10.2%) 0/65 (0%)
    Photopsia 1/136 (0.7%) 29/137 (21.2%) 0/65 (0%)
    Visual Impairment 1/136 (0.7%) 23/137 (16.8%) 0/65 (0%)
    Gastrointestinal disorders
    Diarrhoea 78/136 (57.4%) 77/137 (56.2%) 17/65 (26.2%)
    Nausea 44/136 (32.4%) 81/137 (59.1%) 11/65 (16.9%)
    Vomiting 30/136 (22.1%) 59/137 (43.1%) 9/65 (13.8%)
    Constipation 26/136 (19.1%) 57/137 (41.6%) 10/65 (15.4%)
    Abdominal Pain 18/136 (13.2%) 20/137 (14.6%) 0/65 (0%)
    Dyspepsia 15/136 (11%) 23/137 (16.8%) 0/65 (0%)
    Stomatitis 12/136 (8.8%) 9/137 (6.6%) 5/65 (7.7%)
    Abdominal Pain Upper 11/136 (8.1%) 26/137 (19%) 0/65 (0%)
    Dry Mouth 8/136 (5.9%) 6/137 (4.4%) 0/65 (0%)
    Dysphagia 2/136 (1.5%) 12/137 (8.8%) 0/65 (0%)
    Gastrooesophageal Reflux Disease 1/136 (0.7%) 16/137 (11.7%) 0/65 (0%)
    General disorders
    Fatigue 28/136 (20.6%) 31/137 (22.6%) 9/65 (13.8%)
    Pyrexia 20/136 (14.7%) 22/137 (16.1%) 9/65 (13.8%)
    Asthenia 18/136 (13.2%) 26/137 (19%) 8/65 (12.3%)
    Oedema Peripheral 13/136 (9.6%) 63/137 (46%) 6/65 (9.2%)
    Non-Cardiac Chest Pain 11/136 (8.1%) 10/137 (7.3%) 0/65 (0%)
    Malaise 7/136 (5.1%) 3/137 (2.2%) 0/65 (0%)
    Influenza Like Illness 6/136 (4.4%) 11/137 (8%) 10/65 (15.4%)
    Peripheral Swelling 5/136 (3.7%) 8/137 (5.8%) 0/65 (0%)
    Infections and infestations
    Upper Respiratory Tract Infection 18/136 (13.2%) 12/137 (8.8%) 6/65 (9.2%)
    Nasopharyngitis 12/136 (8.8%) 15/137 (10.9%) 5/65 (7.7%)
    Urinary Tract Infection 10/136 (7.4%) 11/137 (8%) 5/65 (7.7%)
    Pneumonia 10/136 (7.4%) 5/137 (3.6%) 6/65 (9.2%)
    Respiratory Tract Infection 7/136 (5.1%) 3/137 (2.2%) 0/65 (0%)
    Investigations
    Blood Creatine Phosphokinase Increased 68/136 (50%) 23/137 (16.8%) 31/65 (47.7%)
    Aspartate Aminotransferase Increased 35/136 (25.7%) 36/137 (26.3%) 17/65 (26.2%)
    Alanine Aminotransferase Increased 31/136 (22.8%) 49/137 (35.8%) 11/65 (16.9%)
    Lipase Increased 31/136 (22.8%) 23/137 (16.8%) 18/65 (27.7%)
    Amylase Increased 25/136 (18.4%) 13/137 (9.5%) 14/65 (21.5%)
    Blood Alkaline Phosphatase Increased 17/136 (12.5%) 18/137 (13.1%) 4/65 (6.2%)
    Blood Cholesterol Increased 13/136 (9.6%) 1/137 (0.7%) 5/65 (7.7%)
    Blood Creatinine Increased 8/136 (5.9%) 20/137 (14.6%) 0/65 (0%)
    Electrocardiogram Qt Prolonged 8/136 (5.9%) 8/137 (5.8%) 5/65 (7.7%)
    Blood Lactate Dehydrogenase Increased 7/136 (5.1%) 5/137 (3.6%) 0/65 (0%)
    Gamma-Glutamyltransferase Increased 5/136 (3.7%) 8/137 (5.8%) 0/65 (0%)
    Neutrophil Count Decreased 3/136 (2.2%) 14/137 (10.2%) 0/65 (0%)
    Amylase Increased 0/136 (0%) 0/137 (0%) 14/65 (21.5%)
    Blood Insulin Increased 0/136 (0%) 0/137 (0%) 4/65 (6.2%)
    Metabolism and nutrition disorders
    Decreased Appetite 16/136 (11.8%) 28/137 (20.4%) 7/65 (10.8%)
    Hyperglycaemia 7/136 (5.1%) 6/137 (4.4%) 0/65 (0%)
    Hypophosphataemia 7/136 (5.1%) 5/137 (3.6%) 0/65 (0%)
    Hypokalaemia 7/136 (5.1%) 1/137 (0.7%) 0/65 (0%)
    Hypercholesterolaemia 7/136 (5.1%) 0/137 (0%) 0/65 (0%)
    Hypocalcaemia 3/136 (2.2%) 11/137 (8%) 0/65 (0%)
    Hypoalbuminaemia 1/136 (0.7%) 11/137 (8%) 0/65 (0%)
    Musculoskeletal and connective tissue disorders
    Back Pain 35/136 (25.7%) 22/137 (16.1%) 11/65 (16.9%)
    Arthralgia 27/136 (19.9%) 17/137 (12.4%) 9/65 (13.8%)
    Muscle Spasms 20/136 (14.7%) 15/137 (10.9%) 17/65 (26.2%)
    Musculoskeletal Pain 15/136 (11%) 11/137 (8%) 10/65 (15.4%)
    Myalgia 14/136 (10.3%) 11/137 (8%) 11/65 (16.9%)
    Musculoskeletal Chest Pain 12/136 (8.8%) 10/137 (7.3%) 0/65 (0%)
    Pain In Extremity 9/136 (6.6%) 19/137 (13.9%) 9/65 (13.8%)
    Muscular Weakness 0/136 (0%) 0/137 (0%) 5/65 (7.7%)
    Nervous system disorders
    Headache 31/136 (22.8%) 25/137 (18.2%) 16/65 (24.6%)
    Dizziness 23/136 (16.9%) 29/137 (21.2%) 12/65 (18.5%)
    Paraesthesia 12/136 (8.8%) 9/137 (6.6%) 5/65 (7.7%)
    Dysgeusia 5/136 (3.7%) 20/137 (14.6%) 0/65 (0%)
    Hypoaesthesia 3/136 (2.2%) 9/137 (6.6%) 0/65 (0%)
    Taste Disorder 3/136 (2.2%) 8/137 (5.8%) 0/65 (0%)
    Psychiatric disorders
    Insomnia 14/136 (10.3%) 12/137 (8.8%) 7/65 (10.8%)
    Depression 5/136 (3.7%) 8/137 (5.8%) 0/65 (0%)
    Anxiety 0/136 (0%) 0/137 (0%) 4/65 (6.2%)
    Respiratory, thoracic and mediastinal disorders
    Cough 49/136 (36%) 29/137 (21.2%) 16/65 (24.6%)
    Dyspnoea 31/136 (22.8%) 26/137 (19%) 8/65 (12.3%)
    Oropharyngeal Pain 13/136 (9.6%) 7/137 (5.1%) 8/65 (12.3%)
    Productive Cough 12/136 (8.8%) 10/137 (7.3%) 8/65 (12.3%)
    Epistaxis 9/136 (6.6%) 0/137 (0%) 0/65 (0%)
    Dysphonia 8/136 (5.9%) 6/137 (4.4%) 0/65 (0%)
    Rhinorrhoea 7/136 (5.1%) 5/137 (3.6%) 0/65 (0%)
    Pleural Effusion 2/136 (1.5%) 9/137 (6.6%) 0/65 (0%)
    Haemoptysis 0/136 (0%) 0/137 (0%) 4/65 (6.2%)
    Skin and subcutaneous tissue disorders
    Pruritus 28/136 (20.6%) 8/137 (5.8%) 6/65 (9.2%)
    Rash 25/136 (18.4%) 4/137 (2.9%) 6/65 (9.2%)
    Dermatitis Acneiform 13/136 (9.6%) 3/137 (2.2%) 5/65 (7.7%)
    Rash Erythematous 9/136 (6.6%) 1/137 (0.7%) 0/65 (0%)
    Dry Skin 8/136 (5.9%) 6/137 (4.4%) 0/65 (0%)
    Rash Maculo-Papular 8/136 (5.9%) 5/137 (3.6%) 9/65 (13.8%)
    Eczema 8/136 (5.9%) 3/137 (2.2%) 6/65 (9.2%)
    Vascular disorders
    Hypertension 44/136 (32.4%) 12/137 (8.8%) 15/65 (23.1%)
    Hypotension 3/136 (2.2%) 10/137 (7.3%) 0/65 (0%)
    Deep Vein Thrombosis 0/136 (0%) 9/137 (6.6%) 0/65 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.

    Results Point of Contact

    Name/Title Study Director
    Organization Takeda
    Phone +1-877-825-3327
    Email TrialDisclosures@takeda.com
    Responsible Party:
    Ariad Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02737501
    Other Study ID Numbers:
    • AP26113-13-301
    • U1111-1210-4363
    • 2015-003447-19
    First Posted:
    Apr 14, 2016
    Last Update Posted:
    Aug 20, 2021
    Last Verified:
    Jul 1, 2021