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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02737501
Other study ID # AP26113-13-301
Secondary ID U1111-1210-43632
Status Completed
Phase Phase 3
First received
Last updated
Start date May 26, 2016
Est. completion date January 29, 2021

Study information

Verified date July 2021
Source Takeda
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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).


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.


Recruitment information / eligibility

Status Completed
Enrollment 275
Est. completion date January 29, 2021
Est. primary completion date July 28, 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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.

Study Design


Intervention

Drug:
Brigatinib
Brigatinib tablets
Crizotinib
Crizotinib tablets

Locations

Country Name City State
Australia Monash Medical Centre Bentleigh East Victoria
Australia Saint Vincent's Hospital Melbourne Fitzroy Victoria
Australia Saint George Hospital Kogarah New South Wales
Australia Royal North Shore Hospital St Leonards New South Wales
Austria Universitatsklinium St. Polten Sankt Polten Lower Austria
Austria Otto-Wagner-Spital Baumgartner Hohe Vienna
Canada Princess Margaret Cancer Centre Toronto Ontario
Denmark Odense University Hospital Odense C
France Centre de Lutte Contre le Cancer Francois Baclesse CAEN Cedex 5 Basse-normandie
France Centre Hospitalier Intercommunal de Creteil Creteil Ile-de-france
France Hopital Albert Michallon Grenoble Cedex 9 Rhone-alpes
France Centre Leon Berard Lyon Rhone-alpes
France Centre Hospitalier Universitaire Hopital Nord Marseille Cedex 20 Provence Alpes COTE D'azur
France Hopital Tenon Paris Ile-de-france
France Hopital Charles Nicolle Rouen Haute-normandie
Germany Evangelische Lungenklinik Berlin Berlin
Germany Universitatsklinik Freiburg Freiburg Baden-wuerttemberg
Germany Studiengesellschaft Haemato-Onkologie Hamburg Prof. Laack und Partner Hamburg
Germany Thoraxklinik Heidelberg gGmbH Heidelberg Baden-wuerttemberg
Germany Kliniken der Stadt Koeln gGmbH - Krankenhaus Merheim Koln Nordrhein-westfalen
Germany Pius Hospital Oldenburg Oldenburg Niedersachsen
Hong Kong Queen Mary Hospital Hong Kong
Hong Kong Queen Elizabeth Hospital Kowloon
Hong Kong Tuen Mun Hospital Tuen Mun New Territories
Italy Azienda Ospedaliera San Giuseppe Moscati Avellino
Italy Centro di Riferimento Oncologico di Aviano Aviano Pordenone
Italy Istituto Oncologico di Bari Giovanni Paolo II Bari
Italy Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi Bologna
Italy Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola Forli-cesena
Italy Istituto Europeo di Oncologia Milano
Italy Istituto Scientifico Universitario San Raffaele Milano
Italy Azienda Ospedaliera San Gerardo di Monza Monza Monza E Brianza
Italy Istituto Tumori Napoli Fondazione G. Pascale Napoli
Italy Azienda Ospedaliero Universitaria Maggiore della Carita Novara
Italy Azienda Ospedaliera di Perugia - Ospedale S. Maria della Misericordia Perugia
Italy Azienda Unita Sanitaria Locale di Ravenna Ravenna
Italy Policlinico Universitario Campus Bio-Medico Roma
Korea, Republic of Chungbuk National University Hospital Cheongju Chungcheongbuk-do
Korea, Republic of National Cancer Center Goyang-si Gyeonggi-do
Korea, Republic of Seoul National University Bundang Hospital Seongnam-si Gyeonggi-do
Korea, Republic of Asan Medical Center Seoul
Korea, Republic of Samsung Medical Center Seoul
Korea, Republic of Seoul National University Hospital Seoul
Korea, Republic of Severance Hospital Seoul
Korea, Republic of The Catholic University of Korea Seoul
Luxembourg Centre Hospitalier de Luxembourg - Hopital Municipal Luxembourg
Netherlands Antoni van Leeuwenhoekziekenhuis Amsterdam Noord-holland
Netherlands Amphia Ziekenhuis - Locatie Langendijk Breda Breda Noord-brabant
Netherlands Universitair Medisch Centrum Groningen Groningen
Netherlands Isala Klinieken Zwolle Overijssel
Norway Radiumhospitalet Oslo
Singapore National Cancer Centre Singapore Singapore
Singapore National University Hospital Singapore
Singapore OncoCare Cancer Centre Singapore
Spain Hospital General Universitario de Alicante Alicante
Spain Hospital Universitari Germans Trias i Pujol Badalona Barcelona
Spain Hospital Universitario Vall d'Hebron Barcelona
Spain Hospital Teresa Herrera - Materno Infantil La Coruna
Spain Hospital Ramon Y Cajal Madrid
Spain Hospital Universitario La Paz Madrid
Spain Hospital Universitario Puerta de Hierro - Majadahonda Majadahonda Madrid
Spain Hospital Regional Universitario Carlos Haya Malaga Instituto de Neurociencias Clinicas Malaga
Spain Hospital Universitario Central de Asturias Oviedo Asturias
Spain Hospital Universitario Marques de Valdecilla Santander
Spain Hospital Universitario Virgen del Rocio Sevilla
Spain Hospital Clinico Universitario de Valencia Valencia
Sweden Karolinska Universitetssjukhuset Stockholm
Switzerland University Hospital Zurich Zurich
Taiwan China Medical University Hospital Taichung
Taiwan Taichung Veterans General Hospital Taichung
Taiwan National Cheng Kung University Tainan Taipei
Taiwan National Taiwan University Hospital Taipei
Taiwan Taipei Veterans General Hospital Taipei
United Kingdom Leicester Royal Infirmary Leicester England
United Kingdom Guy's and Saint Thomas' NHS Foundation Trust London England
United Kingdom Royal Marsden NHS Trust London England
United Kingdom University College London London England
United Kingdom Maidstone Hospital Maidstone England
United Kingdom The Christie NHS Foundation Trust Manchester England
United States University of Colorado Cancer Center Aurora Colorado
United States Kaiser Permanente Bellflower Medical Offices Bellflower California
United States Beth Israel Deaconess Medical Center Boston Massachusetts
United States Rocky Mountain Cancer Centers - Boulder Boulder Colorado
United States Montefiore Medical Center Bronx New York
United States Oncology Hematology Care - Blue Ash Cincinnati Ohio
United States Minnesota Oncology Coon Rapids Minnesota
United States Sylvester Comprehensive Cancer Center Deerfield Beach Florida
United States Virginia Cancer Specialists - Fairfax Office Fairfax Virginia
United States West Michigan Cancer Center Kalamazoo Michigan
United States Stephenson Cancer Center Oklahoma City Oklahoma
United States USOR - Arizona Oncology Associates - Sedona Sedona Arizona

Sponsors (1)

Lead Sponsor Collaborator
Ariad Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Denmark,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Luxembourg,  Netherlands,  Norway,  Singapore,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Progression-free Survival (PFS) 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. Up to end of study (Up to 56 months)
Secondary Confirmed Objective Response Rate (ORR) 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. Baseline up to end of treatment (Up to 36 months)
Secondary Confirmed Intracranial ORR (iORR) 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. Baseline up to end of treatment (Up to 36 months)
Secondary Intracranial Progression Free Survival 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. Baseline up to end of study (Up to 56 months)
Secondary Overall Survival (OS) Overall survival is defined as the time from randomization until death due to any cause. Baseline up to end of study (Up to 56 months)
Secondary Duration of Response (DOR) 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. Baseline up to end of study (Up to 56 months)
Secondary Time to Response (TTR) 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. Baseline up to end of treatment (Up to 36 months)
Secondary Disease Control Rate (DCR) 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. Baseline up to end of treatment (Up to 36 months)
Secondary Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) 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. From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)
Secondary Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) 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. Baseline and Month 36
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