Clinical trial NCT03596866: A Study of Brigatinib Compared to Alectinib in Adults With Non-Small-Cell Lung Cancer
Official title: A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIG®) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: ALK+ Advanced NSCLC
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-07-24
Enrollment: 248
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Brigatinib is a medicine that binds to the surface of tumor cells in some cancers and delivers a dose of chemotherapy directly to the tumor. In this study, participants will be people with non-small-cell lung cancer (NSCLC for short). The main aim of the study is to learn if brigatinib stops the tumors from growing, or if the tumors have shrunk or disappeared, compared to a medicine called alectinib.

At the first visit, the study doctor will check who can take part. Participants who can take part will be picked for 1 of 2 treatments by chance:

* Brigatinib tablets
* Alectinib capsules

All participants will take brigatinib or alectinib at about the same time every day. They will continue with treatment throughout the study unless their cancer gets worse, they have side effects from the treatment, they leave the study for certain reasons, or the study is stopped.

After stopping treatment, participants will visit the study clinic for a check-up 30 days later.

Detailed description: The drug being tested in this study is called brigatinib. Brigatinib has been demonstrated to benefit people with anaplastic lymphoma kinase-positive (ALK+) NSCLC.

The comparator drug is called alectinib. Alectinib has been demonstrated to benefit people with ALK+ NSCLC. Both drugs belong to a class of drugs called anaplastic lymphoma kinase (ALK) inhibitors. Both drugs are taken by mouth. Both drugs are approved by the United States Food and Drug Administration (US FDA).

The study will enroll approximately 246 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1 ratio to one of the two treatment groups:

* Brigatinib
* Alectinib

All participants will be asked to take brigatinib or alectinib at the same time each day throughout the study. For each participant eligible to continue in the study and to facilitate the remaining participants from Brigatinib-2002 (NCT03535740) to have continued treatment access, the study extension phase may be initiated for participants to continue receiving their randomized study treatment (i.e., brigatinib or alectinib) until they meet at least one of the treatment discontinuation criteria.

This multi-center trial will be conducted in the United States, Argentina, Austria, Canada, Chile, China, Croatia, France, Germany, Greece, Hong Kong, Italy, Mexico, Romania, Russia, South Korea, Spain, Sweden, Taiwan, and Thailand. The overall time to participate in this study is 5 years. Participants will make multiple visits to the clinic, and 30 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
2. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC.
3. Must meet one of the following criteria:

   * Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine's FoundationOne CDx.
   * Have documented ALK rearrangement by a different test and be able to provide tumor sample to the central laboratory. (Note: central laboratory ALK rearrangement testing results are not required to be obtained before randomization).
4. Had PD while on crizotinib, as assessed by the investigator or treating physician except for participants previously participating in the Brigatinib-2002 study (Note: crizotinib does not need to be the last therapy a participant received. The participant may have received chemotherapy as his/her last therapy).
5. Treatment with crizotinib for at least 4 weeks before progression except for participants previously participating in the Brigatinib-2002 study.
6. Have had no other ALK inhibitor other than crizotinib except for participants previously participating in the Brigatinib-2002 study.
7. Have had no more than 2 prior regimens of systemic anticancer therapy (other than crizotinib) in the locally advanced or metastatic setting. Note: a systemic anticancer therapy regimen will be counted if it is administered for at least 1 complete cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen. Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior regimen if disease progression/recurrence occurred within 12 months upon completion of this neoadjuvant or adjuvant therapy. (Systemic therapy followed by maintenance therapy will be considered as one regimen if the maintenance therapy consists of a drug or drugs that were used in the regimen that immediately preceded maintenance).
8. Have at least 1 measurable (that is, target) lesion per RECIST v1.1.
9. Have recovered from toxicities related to prior anticancer therapy to national cancer institute common terminology criteria for adverse events (NCI CTCAE) version 4.03 grade less than or equal to (\<=)1. (Note: treatment-related alopecia or peripheral neuropathy that are grade greater than (\>) 1 are allowed, if deemed irreversible).
10. Have adequate organ function, at the time of initial screening, except for participants previously participating in the Brigatinib-2002 study as determined by:

    * Total bilirubin \<=1.5 times the upper limit of normal (ULN).
    * Estimated glomerular filtration rate greater than equal to (\>=) 30 milliliter per minute (mL/min)/1.73 square meter \[m\^2\], using the modification of diet in renal disease equation.
    * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \<=2.5\*ULN; \<=5\*ULN is acceptable if liver metastases are present.
    * Serum lipase \<=1.5\*ULN.
    * Platelet count \>=75\*10\^9 per liter \[/L\].
    * Hemoglobin \>=9 gram per deciliter (g/dL).
    * Absolute neutrophil count \>=1.5\*10\^9 / L.
11. Suitable venous access for study-required blood sampling (that is, including pharmacokinetic \[PK\] and laboratory safety tests).

Exclusion Criteria:

1. Had participated in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L) \[NCT02737501\].
2. Had received crizotinib within 7 days before randomization.
3. Have a history or presence at baseline of pulmonary interstitial disease, drug related pneumonitis, or radiation pneumonitis.
4. Have uncontrolled hypertension. Participants with hypertension should be under treatment for control of blood pressure upon study entry.
5. Had received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days before randomization.
6. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before randomization.
7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic 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. Had received chemotherapy or radiation therapy within 14 days before randomization except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
9. Had received antineoplastic monoclonal antibodies within 30 days of randomization.
10. Had major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
11. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (participants with asymptomatic brain metastases or participants who have stable symptoms and did not require an increased dose of corticosteroids to control symptoms within 7 days before randomization will be enrolled). Note: If a participant has worsening neurological symptoms or signs due to CNS metastasis, the participant needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7 days before randomization.
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.
13. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to the following:

    * Myocardial infarction within 6 months before randomization.
    * Unstable angina within 6 months before randomization.
    * New York Heart Association Class III or IV heart failure within 6 months before randomization.
    * History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician.
    * Any history of clinically significant ventricular arrhythmia.
14. Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of study drug.
15. Have malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug.
16. Have an ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics.
17. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history.
18. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. Testing is not required in the absence of history.
19. Any serious medical condition or psychiatric illness that could, in the investigator's opinion, potentially compromise participant safety or interfere with the completion of treatment according to this protocol.
20. Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.
21. Life-threatening illness unrelated to cancer.
22. Female participants who are lactating and breastfeeding.
23. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

Primary outcomes:
measure: Progression-free Survival (PFS) as Assessed by Blinded Independent Review Committee (BIRC) Per RECIST v1.1
timeFrame: Up to 33.8 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 5 years
measure: PFS as Assessed by Investigator Per RECIST v1.1
timeFrame: 5 years
measure: Objective Response Rate (ORR) as Assessed by Investigator and BIRC Per RECIST v1.1
timeFrame: 5 years
measure: Duration of Response (DOR) as Assessed by Investigator and BIRC Per RECIST v1.1
timeFrame: 5 years
measure: Time to Response as Assessed by Investigator and BIRC Per RECIST v1.1
timeFrame: 5 years
measure: Intracranial Objective Response Rate (iORR) as Assessed by BIRC Per Modified RECIST v1.1
timeFrame: 5 years
measure: Intracranial Duration of Response (iDOR) as Assessed by the BIRC Per Modified RECIST v1.1
timeFrame: 5 years
measure: Time to Intracranial Disease Progression (iPD) as Assessed by BIRC Per Modified RECIST v1.1
timeFrame: 5 years
measure: Health-Related Quality of Life (HRQOL) From European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 v3.0) Score
timeFrame: 5 years
measure: HRQOL From EORTC QLQ- Lung Cancer (LC) 13
timeFrame: 5 years
Other outcomes:
Locations:
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Athens
country: United States
facility: University Cancer and Blood Center
state: Georgia
city: Albany
country: United States
facility: New York Oncology Hematology - Albany Medical Center
state: New York
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: San Miguel De Tucuman
country: Argentina
facility: Centro Para la Atencion Integral del Paciente Oncologico
state: Tucuman
city: Cordoba
country: Argentina
facility: Sanatorio Duarte Quiros
city: La Rioja
country: Argentina
facility: Centro Oncologico Riojano Integral
city: Klagenfurt am Worthersee
country: Austria
facility: Klinikum Klagenfurt Am Worthersee
state: Carinthia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: Toronto University Health Network
state: Ontario
city: Recoleta
country: Chile
facility: Centro de Investigacion Clinica Bradford Hill
state: Santiago
city: Beijing
country: China
facility: Beijing Chest Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital - East
state: Beijing
city: Beijing
country: China
facility: Peking University Cancer Hospital/Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: The 307th Hospital of Chinese Peoples Liberation Army
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
state: Guangdong
city: Harbin
country: China
facility: Affiliated Tumor Hospital of Harbin Medical University - The 3rd Affiliated Hospital of HMU
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Changchun
country: China
facility: Jilin Provincial Cancer Hospital (Changchun Cancer Hospital)
state: Jilin
city: Shanghai
country: China
facility: Shanghai Chest Hospital
state: Shanghai
city: Tianjin
country: China
facility: Chang Gung Memorial Hospital Linkou Branch
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University
state: Zhejiang
city: Dubrovnik
country: Croatia
facility: Fudan University Shanghai Cancer Center
state: Dubrovnik-Neretva
city: Dubrovnik
country: Croatia
facility: Opca bolnica Dubrovnik
state: Dubrovnik-Neretva
city: Pula
country: Croatia
facility: General Hospital Pula
city: Zagreb
country: Croatia
facility: Klinicki bolnicki centar Sestre milosrdnice
city: Zagreb
country: Croatia
facility: Klinika za Pulmologiju
city: Pessac
country: France
facility: Hopital Haut-Leveque
state: Aquitaine
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal de Creteil
state: Ile-de-france
city: Creteil
country: France
facility: Fudan University Shanghai Cancer Center
state: Ile-de-france
city: Suresnes
country: France
facility: Hopital Foch
state: Ile-de-france
city: Villejuif cedex
country: France
facility: Gustave Roussy
state: Ile-de-france
city: Toulouse Cedex 9
country: France
facility: Centre Hospitalier Universitaire de Toulouse- Hopital Larrey
state: Midi-pyrenees
city: Le Mans Cedex 9
country: France
facility: Centre Hospitalier Le Mans
state: PAYS DE LA Loire
city: Toulon
country: France
facility: Centre Hospitalier Intercommunal Toulon - La Seyne Sur Mer
state: Provence Alpes COTE D'azur
city: Grenoble Cedex 9
country: France
facility: Hopital Albert Michallon
state: Rhone-alpes
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg
state: Baden-wuerttemberg
city: Gauting
country: Germany
facility: Asklepios Fachkliniken Munchen-Gauting
state: Bayern
city: Immenstadt
country: Germany
facility: Klinikum Kempten-Oberallgau
state: Bayern
city: Athens
country: Greece
facility: University General Hospital of Athens Attikon
state: Attica
city: Cholargos
country: Greece
facility: Iaso General Hospital
state: Attica
city: Nea Kifisia
country: Greece
facility: General Oncology Hospital of Kifisia Oi Agioi Anargiroi
state: Attica
city: Thessaloniki
country: Greece
facility: Interbalkan Medical Center of Thessaloniki
state: Macedonia
city: Larissa
country: Greece
facility: University General Hospital of Larissa
state: Thessaly
city: Athens
country: Greece
facility: Sotiria General Hospital for Respiratory Diseases of Attica
city: Chai Wan
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
state: Eastern District
city: Central
country: Hong Kong
facility: Humanity and Health Research Centre
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Kowloon
country: Hong Kong
facility: Hong Kong United Oncology Centre
city: Kowloon
country: Hong Kong
facility: Princess Margaret Hospital
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: Forli-cesena
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico di Aviano
state: Pordenone
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Milano
country: Italy
facility: Istituto Scientifico Universitario San Raffaele
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent's Hospital
state: Gyeonggi-do
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggi-do
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
state: Gyeongsangnam-do
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea - Seoul St. Mary's Hospital
city: Ciudad de Mexico
country: Mexico
facility: Medica Sur
state: Cdmx
city: Aguascalientes
country: Mexico
facility: Centro de Investigacion Medica Aguascalientes
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic Prof. Dr. Ion Chiricu
state: Cluj
city: Timisoara
country: Romania
facility: Oncocenter- Oncologie Clinica
state: Timis
city: Bucuresti
country: Romania
facility: Institutul Oncologic Prof. Dr. Alexandru Trestioreanu Bucaresti
city: Iasi
country: Romania
facility: Centrul de oncologie Euroclinic
city: Arkhangelsk
country: Russian Federation
facility: State Institution of Healthcare Arkhangelsk Regional Clinical Oncology Dispensary
state: Arkhangelr
city: Saint-Petersburg
country: Russian Federation
facility: Euromedservice
state: Saint Petersburg
city: Saint-Petersburg
country: Russian Federation
facility: Saint Petersburg Clinical Scientific and Practical Center of Specialized Types of Medical Aid
state: Saint Petersburg
city: Pyatigorsk
country: Russian Federation
facility: Clinica Ultra Sound Diagnostic 4D
state: Stavropol
city: Irkutsk
country: Russian Federation
facility: Irkutsk Regional Oncology Center
city: Moscow
country: Russian Federation
facility: N.N. Blokhin Russian Cancer Research Center
city: Moscow
country: Russian Federation
facility: VitaMed
city: Moscow
country: Russian Federation
facility: State Budget Institution National Medical Research Center of Radiology of the Ministry of Heal
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital Number 62
city: Omsk
country: Russian Federation
facility: Omsk Regional Clinical Oncologic Dispensary
city: Saint Petersburg
country: Russian Federation
facility: Leningrad Regional Clinical Hospital
city: Saint Petersburg
country: Russian Federation
facility: Center of Palliative Medicine - Devita
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Healthcare Institution Municipal Clinical Oncology Dispensary
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: A Coruna
country: Spain
facility: Hospital Teresa Herrera - Materno Infantil
state: LA Coruna
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Reus
country: Spain
facility: Hospital Universitari Sant Joan de Reus
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset - Solna
state: Stockholm
city: Uppsala
country: Sweden
facility: Uppsala Akademiska Sjukhus
city: Changhua City
country: Taiwan
facility: Changhua Christian Hospital
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Tainan City
country: Taiwan
facility: Chi Mei Hospital Liouying
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital Linkou Branch
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
state: Bangkok Metropolis
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital
state: Bangkok Metropolis
city: Songkhla
country: Thailand
facility: Songklanagarind Hospital
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Popat S, Liu G, Lu S, Song G, Ma X, Yang JC. Brigatinib vs alectinib in crizotinib-resistant advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALTA-3). Future Oncol. 2021 Nov;17(32):4237-4247. doi: 10.2217/fon-2021-0608. Epub 2021 Aug 23.