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

Phase 3

Completed

• Conditions: Non-small Cell Lung Cancer; Advanced Malignancies; Lung Cancer; Carcinoma
• Interventions: Drug: Crizotinib; Drug: Brigatinib

• Registration Number: NCT02737501
• Lead Sponsor: Ariad Pharmaceuticals

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 Timeline

• Study First Submitted: 2016-03-30
• Study First Submitted QC: 2016-04-11
• Study First Posted: 2016-04-14
• Study Start: 2016-05-26
• Primary Completion: 2020-07-28
• Study Completion: 2021-01-29
• Status Verified: 2021-07
• Results First Submitted: 2021-07-27
• Results First Submitted QC: 2021-07-27
• Last Update Submitted: 2021-07-27
• Results First Posted: 2021-08-20
• Last Update Posted: 2021-08-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 275

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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Randomized Phase: Crizotinib 250 mg BID	Crizotinib	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).
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	Brigatinib	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).
Randomized Phase: Brigatinib 90 mg QD/180 QD	Brigatinib	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).

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (91)

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

Monash Medical Centre; 🇦🇺 Bentleigh East, Victoria, Australia

Universitatsklinium St. Polten; 🇦🇹 Sankt Polten, Lower Austria, Austria

Maidstone Hospital; 🇬🇧 Maidstone, England, United Kingdom

Universitair Medisch Centrum Groningen; 🇳🇱 Groningen, Netherlands

National Cancer Center; 🇰🇷 Goyang-si, Gyeonggi-do, Korea, Republic of

National University Hospital; 🇸🇬 Singapore, Singapore

OncoCare Cancer Centre; 🇸🇬 Singapore, Singapore

University Hospital Zurich; 🇨🇭 Zurich, Switzerland

National Cheng Kung University; 🇨🇳 Tainan, Taipei, Taiwan

Hospital Universitari Germans Trias i Pujol; 🇪🇸 Badalona, Barcelona, Spain

Centre de Lutte Contre le Cancer Francois Baclesse; 🇫🇷 CAEN Cedex 5, Basse-normandie, France

Studiengesellschaft Haemato-Onkologie Hamburg Prof. Laack und Partner; 🇩🇪 Hamburg, Germany

Kaiser Permanente Bellflower Medical Offices; 🇺🇸 Bellflower, California, United States

Royal North Shore Hospital; 🇦🇺 St Leonards, New South Wales, Australia

Istituto Europeo di Oncologia; 🇮🇹 Milano, Italy

Hopital Tenon; 🇫🇷 Paris, Ile-de-france, France

Hospital General Universitario de Alicante; 🇪🇸 Alicante, Spain

Centre Hospitalier de Luxembourg - Hopital Municipal; 🇱🇺 Luxembourg, Luxembourg

Odense University Hospital; 🇩🇰 Odense C, Denmark

Istituto Scientifico Universitario San Raffaele; 🇮🇹 Milano, Italy

Istituto Tumori Napoli Fondazione G. Pascale; 🇮🇹 Napoli, Italy

Azienda Ospedaliero Universitaria Maggiore della Carita; 🇮🇹 Novara, Italy

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Hospital Teresa Herrera - Materno Infantil; 🇪🇸 La Coruna, Spain

Centro di Riferimento Oncologico di Aviano; 🇮🇹 Aviano, Pordenone, Italy

Taichung Veterans General Hospital; 🇨🇳 Taichung, Taiwan

Policlinico Universitario Campus Bio-Medico; 🇮🇹 Roma, Italy

Saint George Hospital; 🇦🇺 Kogarah, New South Wales, Australia

Hospital Clinico Universitario de Valencia; 🇪🇸 Valencia, Spain

Azienda Ospedaliera San Giuseppe Moscati; 🇮🇹 Avellino, Italy

Istituto Oncologico di Bari Giovanni Paolo II; 🇮🇹 Bari, Italy

Hopital Charles Nicolle; 🇫🇷 Rouen, Haute-normandie, France

Kliniken der Stadt Koeln gGmbH - Krankenhaus Merheim; 🇩🇪 Koln, Nordrhein-westfalen, Germany

Taipei Veterans General Hospital; 🇨🇳 Taipei, Taiwan

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Radiumhospitalet; 🇳🇴 Oslo, Norway

National Cancer Centre Singapore; 🇸🇬 Singapore, Singapore

Hospital Ramon Y Cajal; 🇪🇸 Madrid, Spain

Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi; 🇮🇹 Bologna, Italy

Azienda Ospedaliera di Perugia - Ospedale S. Maria della Misericordia; 🇮🇹 Perugia, Italy

Azienda Unita Sanitaria Locale di Ravenna; 🇮🇹 Ravenna, Italy

Centre Hospitalier Intercommunal de Creteil; 🇫🇷 Creteil, Ile-de-france, France

Pius Hospital Oldenburg; 🇩🇪 Oldenburg, Niedersachsen, Germany

Isala Klinieken; 🇳🇱 Zwolle, Overijssel, Netherlands

Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Queen Elizabeth Hospital; 🇭🇰 Kowloon, Hong Kong

Antoni van Leeuwenhoekziekenhuis; 🇳🇱 Amsterdam, Noord-holland, Netherlands

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; 🇮🇹 Meldola, Forli-cesena, Italy

Azienda Ospedaliera San Gerardo di Monza; 🇮🇹 Monza, Monza E Brianza, Italy

Hospital Universitario Puerta de Hierro - Majadahonda; 🇪🇸 Majadahonda, Madrid, Spain

Seoul National University Bundang Hospital; 🇰🇷 Seongnam-si, Gyeonggi-do, Korea, Republic of

Hospital Universitario Virgen del Rocio; 🇪🇸 Sevilla, Spain

The Catholic University of Korea; 🇰🇷 Seoul, Korea, Republic of

Leicester Royal Infirmary; 🇬🇧 Leicester, England, United Kingdom

Sylvester Comprehensive Cancer Center; 🇺🇸 Deerfield Beach, Florida, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Minnesota Oncology; 🇺🇸 Coon Rapids, Minnesota, United States

Oncology Hematology Care - Blue Ash; 🇺🇸 Cincinnati, Ohio, United States

Stephenson Cancer Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Virginia Cancer Specialists - Fairfax Office; 🇺🇸 Fairfax, Virginia, United States

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

Saint Vincent's Hospital Melbourne; 🇦🇺 Fitzroy, Victoria, Australia

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Asturias, Spain

University College London; 🇬🇧 London, England, United Kingdom

Guy's and Saint Thomas' NHS Foundation Trust; 🇬🇧 London, England, United Kingdom

Royal Marsden NHS Trust; 🇬🇧 London, England, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, England, United Kingdom

USOR - Arizona Oncology Associates - Sedona; 🇺🇸 Sedona, Arizona, United States

Rocky Mountain Cancer Centers - Boulder; 🇺🇸 Boulder, Colorado, United States

Otto-Wagner-Spital Baumgartner Hohe; 🇦🇹 Vienna, Austria

Hopital Albert Michallon; 🇫🇷 Grenoble Cedex 9, Rhone-alpes, France

Centre Hospitalier Universitaire Hopital Nord; 🇫🇷 Marseille Cedex 20, Provence Alpes COTE D'azur, France

Centre Leon Berard; 🇫🇷 Lyon, Rhone-alpes, France

Thoraxklinik Heidelberg gGmbH; 🇩🇪 Heidelberg, Baden-wuerttemberg, Germany

Amphia Ziekenhuis - Locatie Langendijk Breda; 🇳🇱 Breda, Noord-brabant, Netherlands

Hospital Regional Universitario Carlos Haya Malaga Instituto de Neurociencias Clinicas; 🇪🇸 Malaga, Spain

Hospital Universitario Marques de Valdecilla; 🇪🇸 Santander, Spain

Karolinska Universitetssjukhuset; 🇸🇪 Stockholm, Sweden

China Medical University Hospital; 🇨🇳 Taichung, Taiwan

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Chungbuk National University Hospital; 🇰🇷 Cheongju, Chungcheongbuk-do, Korea, Republic of

Universitatsklinik Freiburg; 🇩🇪 Freiburg, Baden-wuerttemberg, Germany

Evangelische Lungenklinik Berlin; 🇩🇪 Berlin, Germany

University of Colorado Cancer Center; 🇺🇸 Aurora, Colorado, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

Queen Mary Hospital; 🇭🇰 Hong Kong, Hong Kong

Tuen Mun Hospital; 🇭🇰 Tuen Mun, New Territories, Hong Kong