Inclusion Criteria:
1. Male or female Japanese patients 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be withdrawn by the patient at any time without prejudice to future medical care.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, patients
must meet 1 of the following 2 criteria:
1. Have documentation of ALK rearrangement by a positive result from the Vysis ALK
Break Apart FISH [fluorescence in situ hybridization] Probe Kit, the Nichirei
Histofine ALK iAEP Kit, or the Ventana ALK (D5F3) 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, patients must meet the following criteria Have
documentation of ALK rearrangement by a positive result from 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 subcohort
based on prior ALK inhibitor treatment. The main cohort includes patients 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 patients will be enrolled. Patients with all other sequences of up to 2 prior
ALK inhibitor(s) may be included in the subcohort, and the number of patients
will be limited to 20.
- Note 2: Patients 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 patients with Gilbert syndrome).
3. Serum creatinine <1.5×ULN. For patients with creatinine levels above or equal to
1.5×ULN, the patient 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/L.
6. Platelet count >=75×10^9/L.
7. Hemoglobin >=9 g/dL.
8. Percutaneous oxygen saturation (SpO2) >=94% without oxygen support. Patients 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 patients 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 patient, 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 patients, 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 patient, 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 VEGFR TKI.
2. The refractory expansion part only: received more than 2 prior ALK inhibitors. Note:
The safety evaluation lead-in part allows patients with any line of prior ALK
inhibitor which includes treatment-naïve patients; however, ALK inhibitor-naïve
patients may be enrolled after the confirmation of first 3 DLT evaluable patients 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 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 patients 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 patient has worsening neurological symptoms or signs due to CNS metastasis,
the patient 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). Patients 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. Patients 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. Patients 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 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: Patients 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. Patients 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 patients who are lactating and breastfeeding or have a positive serum pregnancy
test during the screening period. Note: Female patients 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 patient safety or interfere with the evaluation of brigatinib.
