Phase 2 Study of Brigatinib in Japanese Participants With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC)
Condition: ALK-positive Advanced NSCLC
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Brigatinib
Intervention description: Brigatinib tablet
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 104.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

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

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             be withdrawn by the participant at any time without prejudice to future medical care.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.