A Study of Brigatinib Compared to Alectinib in Adults With Non-Small-Cell Lung Cancer

ALK+ Advanced NSCLC Clinical Trial

— ALTA-3  

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®)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03596866
• Other study ID #: Brigatinib-3001
• Secondary ID: 2018-001957-29
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 19, 2019
• Est. completion date: September 30, 2024

Study information

• Verified date: June 2024
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 248
• Est. completion date: September 30, 2024
• Est. primary completion date: August 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• ALK+ Advanced NSCLC
• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• Brigatinib
Brigatinib Tablets.
• Alectinib
Alectinib Capsules.

Locations

Country	Name	City	State
Argentina	Sanatorio Duarte Quiros	Cordoba
Argentina	Centro Oncologico Riojano Integral	La Rioja
Argentina	Centro Para la Atencion Integral del Paciente Oncologico	San Miguel De Tucuman	Tucuman
Austria	Klinikum Klagenfurt Am Worthersee	Klagenfurt am Worthersee	Carinthia
Canada	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	Toronto University Health Network	Toronto	Ontario
Chile	Centro de Investigacion Clinica Bradford Hill	Recoleta	Santiago
China	Beijing Cancer Hospital	Beijing	Beijing
China	Beijing Chest Hospital	Beijing	Beijing
China	Peking Union Medical College Hospital - East	Beijing	Beijing
China	Peking University Cancer Hospital/Beijing Cancer Hospital	Beijing	Beijing
China	The 307th Hospital of Chinese Peoples Liberation Army	Beijing	Beijing
China	Jilin Provincial Cancer Hospital (Changchun Cancer Hospital)	Changchun	Jilin
China	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong
China	The First Affiliated Hospital, Zhejiang University	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Affiliated Tumor Hospital of Harbin Medical University - The 3rd Affiliated Hospital of HMU	Harbin	Heilongjiang
China	Shanghai Chest Hospital	Shanghai	Shanghai
China	Chang Gung Memorial Hospital Linkou Branch	Tianjin	Tianjin
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin	Tianjin
China	Henan Cancer Hospital	Zhengzhou	Henan
Croatia	Fudan University Shanghai Cancer Center	Dubrovnik	Dubrovnik-Neretva
Croatia	Opca bolnica Dubrovnik	Dubrovnik	Dubrovnik-Neretva
Croatia	General Hospital Pula	Pula
Croatia	Klinicki bolnicki centar Sestre milosrdnice	Zagreb
Croatia	Klinika za Pulmologiju	Zagreb
France	Centre Hospitalier Intercommunal de Creteil	Creteil	Ile-de-france
France	Fudan University Shanghai Cancer Center	Creteil	Ile-de-france
France	Hopital Albert Michallon	Grenoble Cedex 9	Rhone-alpes
France	Centre Hospitalier Le Mans	Le Mans Cedex 9	PAYS DE LA Loire
France	Hopital Haut-Leveque	Pessac	Aquitaine
France	Hopital Foch	Suresnes	Ile-de-france
France	Centre Hospitalier Intercommunal Toulon - La Seyne Sur Mer	Toulon	Provence Alpes COTE D'azur
France	Centre Hospitalier Universitaire de Toulouse- Hopital Larrey	Toulouse Cedex 9	Midi-pyrenees
France	Gustave Roussy	Villejuif cedex	Ile-de-france
Germany	Asklepios Fachkliniken Munchen-Gauting	Gauting	Bayern
Germany	Thoraxklinik Heidelberg	Heidelberg	Baden-wuerttemberg
Germany	Klinikum Kempten-Oberallgau	Immenstadt	Bayern
Greece	Sotiria General Hospital for Respiratory Diseases of Attica	Athens
Greece	University General Hospital of Athens Attikon	Athens	Attica
Greece	Iaso General Hospital	Cholargos	Attica
Greece	University General Hospital of Larissa	Larissa	Thessaly
Greece	General Oncology Hospital of Kifisia Oi Agioi Anargiroi	Nea Kifisia	Attica
Greece	Interbalkan Medical Center of Thessaloniki	Thessaloniki	Macedonia
Hong Kong	Humanity and Health Research Centre	Central
Hong Kong	Pamela Youde Nethersole Eastern Hospital	Chai Wan	Eastern District
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Hong Kong United Oncology Centre	Kowloon
Hong Kong	Princess Margaret Hospital	Kowloon
Italy	Centro di Riferimento Oncologico di Aviano	Aviano	Pordenone
Italy	Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera Universitaria San Martino	Genova
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Forli-cesena
Italy	Istituto Scientifico Universitario San Raffaele	Milano
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli
Italy	Ospedale Santa Maria delle Croci	Ravenna
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si	Chungcheongbuk-do
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Gachon University Gil Medical Center	Incheon	Gyeonggi-do
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea - Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon	Gyeonggi-do
Korea, Republic of	The Catholic University of Korea St. Vincent's Hospital	Suwon-si	Gyeonggi-do
Korea, Republic of	Ulsan University Hospital	Ulsan	Gyeongsangnam-do
Mexico	Centro de Investigacion Medica Aguascalientes	Aguascalientes
Mexico	Medica Sur	Ciudad de Mexico	Cdmx
Romania	Institutul Oncologic Prof. Dr. Alexandru Trestioreanu Bucaresti	Bucuresti
Romania	Institutul Oncologic Prof. Dr. Ion Chiricu	Cluj-Napoca	Cluj
Romania	Centrul de oncologie Euroclinic	Iasi
Romania	Oncocenter- Oncologie Clinica	Timisoara	Timis
Russian Federation	State Institution of Healthcare Arkhangelsk Regional Clinical Oncology Dispensary	Arkhangelsk	Arkhangelr
Russian Federation	Irkutsk Regional Oncology Center	Irkutsk
Russian Federation	Moscow City Oncology Hospital Number 62	Moscow
Russian Federation	N.N. Blokhin Russian Cancer Research Center	Moscow
Russian Federation	State Budget Institution National Medical Research Center of Radiology of the Ministry of Heal	Moscow
Russian Federation	VitaMed	Moscow
Russian Federation	Omsk Regional Clinical Oncologic Dispensary	Omsk
Russian Federation	Clinica Ultra Sound Diagnostic 4D	Pyatigorsk	Stavropol
Russian Federation	Center of Palliative Medicine - Devita	Saint Petersburg
Russian Federation	Leningrad Regional Clinical Hospital	Saint Petersburg
Russian Federation	Saint Petersburg State Healthcare Institution Municipal Clinical Oncology Dispensary	Saint Petersburg
Russian Federation	Euromedservice	Saint-Petersburg	Saint Petersburg
Russian Federation	Saint Petersburg Clinical Scientific and Practical Center of Specialized Types of Medical Aid	Saint-Petersburg	Saint Petersburg
Spain	Hospital Teresa Herrera - Materno Infantil	A Coruna	LA Coruna
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon Y Cajal	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga
Spain	Hospital Universitari Sant Joan de Reus	Reus
Spain	Hospital Universitario Virgen Macarena	Sevilla
Sweden	Karolinska Universitetssjukhuset - Solna	Solna	Stockholm
Sweden	Uppsala Akademiska Sjukhus	Uppsala
Taiwan	Changhua Christian Hospital	Changhua City
Taiwan	Hualien Tzu Chi Hospital	Hualien City
Taiwan	Kaohsiung Medical University Hospital	Kaohsiung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Chi Mei Hospital Liouying	Tainan City
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital Linkou Branch	Taoyuan City
Thailand	King Chulalongkorn Memorial Hospital	Bangkok	Bangkok Metropolis
Thailand	Phramongkutklao Hospital	Bangkok	Bangkok Metropolis
Thailand	Songklanagarind Hospital	Songkhla
United States	New York Oncology Hematology - Albany Medical Center	Albany	New York
United States	University Cancer and Blood Center	Athens	Georgia
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	The Oncology Institute of Hope and Innovation	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Canada,  Chile,  China,  Croatia,  France,  Germany,  Greece,  Hong Kong,  Italy,  Korea, Republic of,  Mexico,  Romania,  Russian Federation,  Spain,  Sweden,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) as Assessed by Blinded Independent Review Committee (BIRC) per RECIST v1.1	PFS is defined as the time interval from the date of randomization until the first date at which disease progression is objectively documented via RECIST v1.1 by BIRC, or death due to any cause, whichever occurs first, in the full analysis set. PFS will be censored for participants without documented disease progression or death at the last valid tumor response assessment.	Up to 5 years
Secondary	Overall Survival (OS)	OS is defined as the time interval from the date of randomization until death due to any cause in the full analysis set. It will be censored on the date of last contact for those participants who are alive.	Up to 5 years
Secondary	PFS as Assessed by Investigator per RECIST v1.1	PFS is defined as the time interval from the date of randomization until the first date at which disease progression is objectively documented via RECIST v1.1 by investigator, or death due to any cause, whichever occurs first, in the full analysis set. PFS will be censored for participants without documented disease progression or death at the last valid tumor response assessment.	Up to 5 years
Secondary	Objective Response Rate (ORR) as Assessed by Investigator and BIRC per RECIST v1.1	ORR is defined as the percentage of the participants who are confirmed to have achieved complete response (CR) or partial response (PR), using RECIST v1.1 after the initiation of study treatment.	Up to 5 years
Secondary	Duration of Response (DOR) as Assessed by Investigator and BIRC	DOR is defined as the time interval from the time that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the progressive disease (PD) is objectively documented or death, as assessed by the investigator and BIRC, using RECIST v1.1.	Up to 5 years
Secondary	Time to Response as Assessed by Investigator and BIRC	Time to response is defined as the time interval from randomization until the initial observation of CR or PR, as assessed by the investigator and BIRC, using RECIST v1.1. Time to response will be summarized using descriptive statistics in participants with confirmed objective response.	Up to 5 years
Secondary	Intracranial Objective Response Rate (iORR) as Assessed by BIRC per Modified RECIST v1.1	iORR, as assessed by the BIRC, is defined as the percentage of the participants who have achieved CR or PR in the central nervous system (CNS) per a modification RECIST v1.1 after the initiation of study treatment in participants with CNS metastases at baseline.	Up to 5 years
Secondary	Intracranial Duration of Response (iDOR) as Assessed by the BIRC per Modified RECIST v1.1	iDOR, as assessed by the BIRC per modified RECIST v1.1, is defined as the time interval from the time that the measurement criteria are first met for CR or PR in the CNS (whichever is first recorded) until the first date that the PD in the CNS is objectively documented or death.	Up to 5 years
Secondary	Time to Intracranial Disease Progression (iPD) as Assessed by BIRC per Modified RECIST v1.1	Time to iPD, as assessed by the BIRC, is defined as the time interval from the date of randomization until the first date at which iPD is objectively documented via a modification of RECIST v1.1. Time to iPD will be censored for participants without documented iPD at the last valid intracranial tumor response assessment.	Up to 5 years
Secondary	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	EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better quality of life (QOL); for the symptom scales, lower scores represent better QOL.	First dose of study drug up to 30 days after last dose (approximately 5 years)
Secondary	HRQOL from EORTC QLQ- Lung Cancer (LC) 13	HRQOL scores will be assessed with European Organization for Research and Treatment (EORTC), its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity.	First dose of study drug up to 30 days after last dose (approximately 5 years)

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