This is a single arm phase II study of brigatinib alone for patients with brain metastases
from anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), who have
either not been treated previously with a tyrosine kinase inhibitor (TKI) targeting ALK or
who have had prior exposure to crizotinib.
In this single-arm phase II trial, patients with brain metastases from ALK+ NSCLC will be
treated with brigatinib alone without upfront brain irradiation. Patients will have close
monitoring with clinical follow up visits and brain magnetic resonance imaging (MRI)
surveillance, which will maximize safety and allow for early treatment if disease progression
is observed. If brigatinib alone can demonstrate high rates of CNS disease control, these
data could support a strategy of upfront brigatinib alone for carefully selected patients
with brain metastases from ALK+ NSCLC.
1. Provision to sign and date the consent form.
2. Stated willingness to comply with all study procedures and be available for the
duration of the study.
3. Ability to take and retain oral medications.
4. Age ≥18 years.
5. Patients with ALK+ lung cancer with evidence of ≥1 previously untreated brain
metastases on brain MRI. Prior therapy (radiation or surgery) for brain metastases is
allowed. However, patients must have ≥1 previously untreated at the time of
6. Patients may be ALK TKI naïve OR have had prior crizotinib therapy.
7. Patients may be included if they are asymptomatic from their brain metastases
(RTOG/EORTC grade 0) or if they have mild symptoms from their brain metastases not to
exceed RTOG/ EORTC grade 1 or 2 (Grade 1: Fully functional status (i.e. able to work)
with minor neurological findings, no medication needed; Grade 2: Neurological findings
present sufficient to require home care / nursing assistance may be required /
medications including steroids/anti-seizure agents may be required) (Cox, James D., et
al "Toxicity criteria of the radiation therapy oncology group (RTOG) and the European
organization for research and treatment of cancer (EORTC)." International Journal of
Radiation Oncology• Biology• Physics 31.5 (1995): 1341-1346).
8. Neurologically symptomatic patients must not require immediate surgical or radiation
therapy for their symptoms, as decided by an investigator.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
10. Have adequate organ function, as determined by
- ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable if liver
metastases are present
- Total serum bilirubin ≤1.5 × ULN (<3.0×ULN for patients with Gilbert syndrome)
- Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the
modification of diet in renal disease (MDRD) equation
- Serum lipase/amylase ≤1.5 × ULN
- Absolute neutrophil count (ANC) ≥1.5 × 109/L
- Platelet count ≥75 × 109/L
- Hemoglobin ≥9 g/dL
11. For females of childbearing potential, have a negative pregnancy test documented prior
to initiating brigatinib.
12. For female and male patients who are fertile, agree to use 2 effective methods of
contraception with their sexual partners from the time of signing the informed consent
through 4 months after the last dose of study drug, or agree to completely abstain
from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal
contraceptives, therefore, women are recommended to use non-hormonal methods of
contraception. Highly effective non-hormonal birth control for women of child bearing
potential with male partners includes:
- Sexual abstinence (no sexual intercourse)
- Intrauterine device (IUD) or intrauterine system (IUS)
- Bilateral tubal ligation (both tubes tied)
- Vasectomized partner
13. Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree
to 1 of the following:
- Practice effective barrier contraception during the entire study treatment period
and through 4 months after the last dose of study drug, or completely abstain
from heterosexual intercourse.
1. Patients who have received prior brigatinib therapy or other CNS-penetrant ALK TKIs,
including alectinib, lorlatinib, or ceritinib.
2. RTOG/EORTC Acute CNS symptoms, grade 3 and 4 (Grade 3: Neurological findings requiring
hospitalization for initial management; Grade 4: Serious neurological impairment that
includes paralysis, coma, or seizures > 3 per week despite medication /
3. Currently pregnant, planning a pregnancy during the study period, or breastfeeding.
4. Have clinically significant, uncontrolled cardiovascular disease per investigator,
specifically including, but not restricted to:
1. Myocardial infarction (MI) within 6 months prior to the first dose of study drug
2. Unstable angina within 6 months prior to first dose of study drug
3. Clinically significant congestive heart failure (CHF) within 6 months prior to
first dose of study drug
4. History of clinically significant atrial or ventricular arrhythmia (including
clinically significant bradyarrhythmia), as determined by the treating physician
5. Cerebrovascular accident or transient ischemic attack within 6 months prior to
first dose of study drug
5. Have uncontrolled hypertension per the investigator. Patients with persistent
hypertension of systolic ≥140 or diastolic ≥90 mm Hg should be under treatment on
study entry to control blood pressure.
6. Have a history or the presence at baseline of pulmonary interstitial disease,
drug-related pneumonitis, or radiation pneumonitis.
7. Have an ongoing or active infection, including, but not limited to, the requirement
for intravenous (IV) antibiotics.
8. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not
required in the absence of history.
9. Have a known or suspected hypersensitivity to brigatinib or its excipients.
10. Additional systemic therapies for the treatment of lung cancer may not be taken
concomitantly with brigatinib (eg, TKIs, immunotherapy, chemotherapy). No washout
period is required for prior therapy.
11. Have malabsorption syndrome or other GI illness that could affect oral absorption of
12. Have any condition or illness that, in the opinion of the investigator, would
compromise patient safety or interfere with the evaluation of brigatinib.
13. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong
cyp3a inducers, or moderate cyp3a inducers within 14 days before enrollment.
14. Had major surgery within 30 days of the first dose of brigatinib. Minor surgical
procedures such as catheter placement or minimally invasive biopsies are allowed.
15. 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 patients with another primary malignancy who
are definitively relapse-free with at least 3 years elapsed since the diagnosis of the
other primary malignancy.