Phase 2 Study of Brigatinib in Japanese Participants With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study is to evaluate efficacy and safety of brigatinib in Japanese participants with anaplastic lymphoma kinase (ALK)-positive NSCLC.

The drug being tested in this study is called brigatinib. Brigatinib is being tested in participants with ALK-positive NSCLC in order to evaluate efficacy and safety of oral doses of brigatinib in Japanese participants with ALK-positive NSCLC.

The study will enroll approximately 110 participants. Participants will be enrolled in non-randomized and opened manner:

- Brigatinib 90 mg for the first 7 days, followed by Brigatinib 180 mg of Brigatinib tablets, once daily in a 28-days cycle.

All participants will be asked to take tablets of brigatinib once daily with or without food throughout the study.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 53 months. Participants will make multiple visits to the clinic during the treatment period, and posttreatment period including a follow-up assessment after last dose of study drug.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female Japanese participants aged \>=20 years on the day of consent.
2. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
3. Have histologically or cytologically confirmed stage IIIB, stage IIIC (locally advanced or recurrent and not a candidate for definitive multimodality therapy), or stage IV NSCLC.
4. Have documentation of ALK rearrangement that meets following criteria.

   For the Safety Evaluation Lead-in Part and the Refractory Expansion Part, participants must meet 1 of the following 2 criteria:
   1. Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK (D5F3) Companion Diagnostics (CDx) Assay at any time during prior disease course. The sponsor may require an adequate tissue available for central laboratory testing by the Vysis ALK Break Apart FISH test if a documented ALK rearrangement is confirmed by a positive result from the Nichirei Histofine ALK iAEP Kit "ONLY".
   2. Had a documented ALK rearrangement by a different test at any time during prior disease course, and adequate tissue available for central laboratory testing by the Vysis ALK Break Apart FISH test. Central confirmation of ALK rearrangement is not required before enrollment.

   For TKI-naïve Expansion Cohort, participants must meet the following criteria Have documentation of ALK rearrangement by a positive result from Ministry of Health, Labour and Welfare (MHLW) Approved tests (e.g Vysis ALK Break Apart FISH Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK \[D5F3\] CDx Assay) prior to enrollment, and required to submit sufficient tumor tissue for central laboratory testing upon request of sponsor. Central confirmation of ALK rearrangement is not required before enrollment
5. The Refractory Expansion Part only: had documented progressive disease (PD) during treatment or within 30 days after discontinuation of treatment with ALK inhibitor.

   * Note 1: The Refractory Expansion Part consists of the Main Cohort and a Sub-cohort based on prior ALK inhibitor treatment. The Main Cohort includes participants who had previously received alectinib (as their only ALK inhibitor) or both crizotinib and alectinib (regardless the sequence of those 2 ALK inhibitors), and a total of 47 participants will be enrolled. Participants with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the Sub-cohort, and the number of participants will be limited to 20.
   * Note 2: Participants who will be included in the Main Cohort of the refractory should have documented PD during treatment or within 30 days after discontinuation of treatment with alectinib.
6. Have at least 1 measurable (ie, target) lesion per RECIST version 1.1. Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy. Brain lesions may not be used as target lesions if they were 1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical resection.
7. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Grade =\<1. Note: Treatment-related alopecia is allowed.
8. Have a life expectancy of \>=3 months.
9. Have adequate organ and hematologic function, as determined by:

   1. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\<2.5 times the upper limit of the normal range (ULN) (=\<5×ULN is acceptable if liver metastases are present).
   2. Total serum bilirubin =\<1.5×ULN (\<3.0×ULN for participants with Gilbert syndrome).
   3. Serum creatinine \<1.5×ULN. For participants with creatinine levels above or equal to 1.5×ULN, the participant is eligible if the estimated creatinine clearance using the Cockcroft-Gault formula is \>=30 mL/minute.
   4. Serum lipase =\<1.5×ULN and serum amylase =\<1.5×ULN.
   5. Absolute neutrophil count (ANC) \>=1.5×10\^9/Liter (L).
   6. Platelet count \>=75×10\^9/L.
   7. Hemoglobin \>=9 gram (g)/ deciliter (dL).
   8. Percutaneous oxygen saturation (SpO2) \>=94% without oxygen support. Participants who need oxygen support are excluded.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of =\<2.
11. Must meet the following criteria:

    1. Female participants who:

       * Are postmenopausal for at least 1 year before the screening visit, OR
       * Are surgically sterile, OR
       * If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
       * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, from the time of signing the informed consent through 4 months after that last dose of study drug. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    2. Male participants, even if surgically sterilized (ie, status postvasectomy), who:

       * Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, OR
       * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, during the entire study treatment period and through 4 months after that last dose of study drug. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
12. Have the willingness and ability to comply with scheduled visit and study procedures.

Exclusion Criteria:

1. Previously received the following treatments. The Refractory Expansion Part only: received any prior ALK inhibitor not specified in the protocol.

   TKI-naïve Expansion Cohort only: received any prior TKI including but not limited to ALK inhibitor and vascular endothelial growth factor receptor (VEGFR) TKI.
2. The Refractory Expansion Part only: received more than 2 prior ALK inhibitors. Note: The Safety Evaluation Lead-in Part allows participants with any line of prior ALK inhibitor which includes treatment-naïve participants; however, ALK inhibitor-naïve participants may be enrolled after the confirmation of first 3 dose-limiting toxicity (DLT) evaluable participants to have no more than 1 DLT during Cycle 1 by investigator's judgement.
3. The Safety Evaluation Lead-in Part and the Refractory Expansion Part only: received ALK inhibitor within 7 days before the first dose of brigatinib.
4. Previously received more than 1 regimen (more than 3 regimens in the Safety Evaluation Lead-in part) of systemic anticancer therapy (other than ALK inhibitors) for locally advanced or metastatic disease. Note: A systemic anticancer therapy regimen will be counted if it is administered over at least 1 cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen unless it was previously used as initial anticancer therapy. Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior regimen if completion of (neo) adjuvant therapy occurred \<12 months before the first dose of brigatinib.
5. Treatment with any investigational products within 30 days or 5 half-lives of that investigational agent, whichever is longer, before the first dose of brigatinib.
6. Received chemotherapy or radiation within 14 days before the first dose of brigatinib, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
7. Received antineoplastic monoclonal antibodies within 30 days before the first dose of brigatinib.
8. Received systemic treatment with strong inhibitors or strong and moderate inducers of cytochrome P450 (CYP) 3A within 7 days before the first dose of brigatinib.
9. Had major surgery within 30 days before the first dose of brigatinib. Minor surgical procedures such as venous catheter placement or minimally invasive biopsies are allowed.
10. Have been diagnosed with another primary malignancy other than NSCLC, except for the following adequately/definitively treated malignancies: nonmelanoma skin cancer, cervical cancer in situ, nonmetastatic prostate cancer; or participant with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
11. Have symptomatic central nervous system (CNS) metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days before the first dose of brigatinib. 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 symptomatic control) for 7 days before the first dose of brigatinib.
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with asymptomatic leptomeningeal disease and without cord compression are allowed.
13. Have ongoing or history of interstitial lung disease (ILD) (including interstitial pneumonitis, pneumonitis, radiation pneumonitis, drug-related pneumonitis, organized pneumonia, and pulmonary alveolitis).
14. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not limited to:

    1. Myocardial infarction within 6 months before the first dose of brigatinib.
    2. Unstable angina within 6 months before the first dose of brigatinib.
    3. Congestive heart failure within 6 months before the first dose of brigatinib.
    4. Uncontrolled atrial arrhythmias despite appropriate medical therapy.
    5. History of ventricular arrhythmia, including history of ventricular tachycardia, ventricular fibrillation, or torsades de pointes. Participants with premature ventricular contractions are allowed.
    6. Cerebrovascular accident or transient ischemic attack within 6 months before the first dose of brigatinib.
15. Have uncontrolled hypertension. Participants with hypertension should be under treatment at the start of screening and demonstrate adequate control of blood pressure.
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. Hepatitis B surface antigen (HBsAg) positive, detectable hepatitis B viral load, or detectable hepatitis C virus (HCV) infection viral load. Note: Participants who have positive hepatitis B core antibody (HBcAb) or hepatitis B surface antibody (HBsAb) can be enrolled but must have an undetectable hepatitis B viral load. Participants who have positive HCV antibody can be enrolled but must have an undetectable hepatitis C viral load.
19. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of brigatinib.
20. Have a known or suspected hypersensitivity to brigatinib or its excipients.
21. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period. Note: Female participants who are lactating will be excluded, even if they discontinue breastfeeding.
22. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of brigatinib.