ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
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
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:
|
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
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
Inclusion Criteria:
-
Have histologically or cytologically confirmed stage IIIB (and not a candidate for definitive multimodality therapy) or stage four (IV) NSCLC.
-
Must have documented ALK rearrangement.
-
Have sufficient tumor tissue available for central analysis.
-
Have at least 1 measurable (that is, target) lesion per RECIST v1.1.
-
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.
-
Are a male or female participants greater than or equal to (>=)18 years old.
-
Have adequate organ function, as defined by the study protocol.
-
Have Eastern Cooperative Oncology Group (ECOG) performance status <=2.
-
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.
-
For female participants of childbearing potential, have a negative pregnancy test documented prior to randomization.
-
For female and male participants who are fertile, agree to use a highly effective form of contraception, as defined by the study protocol.
-
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.
-
Have the willingness and ability to comply with scheduled visit and study procedures.
Exclusion Criteria:
-
Previously received an investigational antineoplastic agent for NSCLC.
-
Previously received any prior tyrosine kinase inhibitor (TKI), including ALK-targeted TKIs.
-
Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease.
-
Received chemotherapy or radiation within 14 days of first dose of study drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT).
-
Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug.
-
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.
-
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.
-
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.
-
Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.
-
Be pregnant, planning a pregnancy, or breastfeeding.
-
Have significant, uncontrolled, or active cardiovascular disease, as defined by the study protocol.
-
Have uncontrolled hypertension.
-
Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
-
Have an ongoing or active infection.
-
Have a known history of human immunodeficiency virus (HIV) infection.
-
Have a known or suspected hypersensitivity to brigatinib or its excipients and/or crizotinib or its excipients.
-
Have malabsorption syndrome or other gastrointestinal (GI) illness or condition.
-
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.- AP26113-13-301
- U1111-1210-4363
- 2015-003447-19
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
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. |
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). |
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). |
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. |
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
|
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
|
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
|
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). |
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%
|
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
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 |
TrialDisclosures@takeda.com |
- AP26113-13-301
- U1111-1210-4363
- 2015-003447-19