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

Lung Cancer Clinical Trial

— ALTA-1L  

Official title:

A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) Versus Crizotinib in Patients With ALK-positive Advanced Lung Cancer

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
• 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
• 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.

Related Conditions & MeSH terms

• Advanced Malignancies
• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Lung Neoplasms
• Non-small Cell Lung Cancer

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