This early phase I trial studies the side effects and how well local consolidative therapy
(LCT) and brigatinib works in treating patients with non-small cell lung cancer that is stage
IV or has come back (recurrent). Giving LCT, such as surgery and/or radiation, after initial
treatment may kill any remaining tumor cells. Brigatinib may stop the growth of tumor cells
by blocking some of the enzymes needed for cell growth. Giving LCT and brigatinib may work
better in treating patients with non-small cell lung cancer.
PRIMARY OBJECTIVES:
I. To assess the safety, tolerability, and feasibility of brigatinib with local consolidative
therapy (LCT) in tyrosine kinase inhibitor-naive ALK-rearranged advanced (non-small cell lung
cancer) NSCLC.
SECONDARY OBJECTIVES:
I. To determine progression-free survival (PFS) using modified Response Evaluation Criteria
in Solid Tumors (RECIST 1.1) in advanced ALK+ NSCLC patients treated with local consolidative
therapy (LCT) after achieving stable disease or partial response with first-line brigatinib
treatment.
II. To determine overall survival (OS). III. To assess time to progression (TTP) of non-LCT
lesions.
EXPLORATORY OBJECTIVES:
I. To assess time to appearance of new metastatic lesion(s). II. To determine the utility of
pre-treatment, pre-LCT, and post-LCT circulating free tumor deoxyribonucleic acid (DNA)
(cfDNA) as a potential prognostic and predictive biomarkers.
II. To evaluate potential impact of LCT on mechanisms of ALK resistance with molecular
analysis of post-progression biopsies.
OUTLINE:
Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every
28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
Patients then undergo LCT for up to 3 weeks in the absence of disease progression or
unacceptable toxicity. Within 7 days after completion of LCT, patients receive brigatinib PO
QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and every 3 months
for up to 2 years.
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of stage IV non-small cell lung
cancer (NSCLC) (or recurrent NSCLC not a candidate for definitive multimodality
therapy)
- Documented ALK re-arrangement as detected by: (1) Fluorescence in situ hybridization
(FISH), (2) immunohistochemistry (IHC), (3) tissue next generation sequencing (NGS),
or (4) cfDNA NGS
- Subjects can be enrolled as (1) tyrosine kinase inhibitor (TKI) naive or (2) after =<
8 weeks of first-line brigatinib treatment without disease progression
- Candidate for local consolidative therapy to at least one site of residual disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L or at least 1500/cubic millimeters or
at least 1.5 x 10^9/L
- Platelet count at least 75,000/cubic millimeters or at least 75 x 10^9/L
- Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or >= 60 mL/minute for subjects
with creatinine levels > 1.5 x the institutional ULN
- Serum total bilirubin less than or equal to =< 1.5 x ULN or direct bilirubin =< ULN or
direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
except for subjects with liver metastases (mets) for whom ALT and AST should be =< 5 x
ULN
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated PTT (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of anticoagulant
- Female patients of childbearing potential must have a negative pregnancy test
documented at time of screening
- Female patients who: a.) Are postmenopausal for at least 1 year before the screening
visit, OR b.) Are surgically sterile, OR c.) If they are of childbearing potential,
agree to practice 2 effective methods of contraception, 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 completely abstain from heterosexual intercourse
- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: a.)
Agree to practice effective barrier contraception during the entire study treatment
period and through 4 months after the last dose of study drug, or b.) Agree to
completely abstain from heterosexual intercourse
- Have normal QT interval on screening electrocardiography (ECG) evaluation, defined as
QT interval corrected (Fridericia) (QTcF) of ·450 milliseconds (msec) in males or =<
470 msec in females
- Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol
Exclusion Criteria:
- Have been diagnosed with another primary malignancy other than NSCLC, except for
adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively
treated non-metastatic prostate cancer; or patients with another primary malignancy
who are definitively relapse-free with at least 2 years elapsed since the diagnosis of
the other primary malignancy
- Previously received any prior TKI, including ALK-targeted TKIs
- Note: on-going first-line brigatinib use as specified in the Inclusion criteria
is allowed
- Previously received more than 1 regimen of chemotherapy or immunotherapy for locally
advanced or metastatic disease; Note that history of consolidative immunotherapy after
concurrent chemoradiotherapy (for locally advanced disease) is allowed
- Symptomatic central nervous system (CNS) metastasis. Asymptomatic CNS disease
requiring increasing dose of corticosteroids within 7 days prior to study enrollment
is also not permitted
- Have current spinal cord compression (symptomatic or asymptomatic and detected by
radiographic imaging). Patients with leptomeningeal disease and without cord
compression are allowed
- The presence of pulmonary interstitial disease, drug-related pneumonitis, or radiation
pneumonitis at screening
- Have a known or suspected hypersensitivity to brigatinib or its excipients
- Have malabsorption syndrome or other gastrointestinal (GI) illness or condition that
could affect oral absorption of the study drug
- Be pregnant, planning a pregnancy, or breastfeeding
- Have significant, uncontrolled, or active cardiovascular disease, specifically
including, but not restricted to: a.) Myocardial infarction (MI) within 6 months prior
to the first dose of study drug b.) Unstable angina within 6 months prior to first
dose of study drug c.) Decompensated congestive heart failure (CHF) within 6 months
prior to first dose of study drug d.) History of clinically significant atrial
arrhythmia (including clinically significant bradyarrhythmia), as determined by the
treating physician e.) Any history of ventricular arrhythmia f.) Cerebrovascular
accident or transient ischemic attack within 6 months prior to first dose of study
drug
- Have uncontrolled hypertension. Patients with hypertension should be under treatment
on study entry to control blood pressure
- Have an ongoing or active infection, including, but not limited to, the requirement
for intravenous (IV) antibiotics
- Have a known history of human immunodeficiency virus (HIV) infection. Testing is not
required in the absence of history
- Have any condition or illness that, in the opinion of the investigator, would
compromise patient safety or interfere with the evaluation of the study drug
