Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) of brigatinib in patients with advanced solid
tumors harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of brigatinib in patients with advanced solid tumors
harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

II. To assess progression free survival (PFS) and overall survival (OS) in patients with
advanced ALK or ROS1 mutated solid tumors treated with brigatinib.

III. To assess sensitivity and durability of response to brigatinib in different solid tumor
types.

IV. To assess the role of intertumoral and intratumoral heterogeneity in the development of
resistance to brigatinib.

V. To identify candidate genomic (including circulating tumor deoxyribonucleic acid [DNA])
and proteomic biomarkers of tumor sensitivity and resistance to brigatinib using
high-throughput approaches (exome, transcriptome, reverse phase protein array [RPPA]).

TERTIARY OBJECTIVES:

I. Correlation of brigatinib exposure with efficacy and safety. II. Correlation of tumor and
plasma biomarkers with brigatinib efficacy and safety.

OUTLINE:

Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 52 weeks.

Inclusion Criteria:

- Patients with histologically or cytologically confirmed diagnosis of locally advanced
or metastatic solid tumors

- Patients must have activating genomic alterations in ALK or ROS1 (mutations, fusions
or amplifications) by any validated Clinical Laboratory Improvement Act
(CLIA)-certified molecular testing (fluorescence in situ hybridization [FISH],
polymerase chain reaction [PCR] or next-generation sequencing [NGS] data are
acceptable); CLIA validated results from other institutions and commercial diagnostic
labs (e.g. Foundation Medicine) are also acceptable

- Patients with progressive disease on any previous therapy including crizotinib and
other ALK tyrosine kinase inhibitors (TKIs), chemotherapy or immunotherapy

- Patients with locally advanced or metastatic solid tumors who have received no
previous therapy of any kind (i.e. first-line therapy) are eligible

- Patients with brain metastases or metastases elsewhere within the central nervous
system (CNS) are eligible for study; patients must be neurologically stable and
asymptomatic

- Patients with tumor suitable for biopsy (as assessed by trained specialists in
interventional radiology) and medically fit to undergo a biopsy or surgical procedure
will have mandatory pre-treatment tumor biopsy or sampling; however, if patients do
not have a tumor suitable for biopsy but have another tissue (preferably progressive
metastatic site) available for molecular evaluation this will be acceptable

- Patients with solid tumors must have at least 1 measurable lesion per Response
Evaluation Criteria in Solid Tumors (RECIST) version (v)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

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of greater than 3 months

- Patients with multiple malignancies remain eligible

- Patients with an inherited cancer syndrome or a medical/family history suggestive of
an inherited cancer syndrome remain eligible

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
through 4 months after the end of treatment; for women of childbearing potential, a
negative pregnancy test must be documented prior to registration

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 10 g/dL

- Platelet count >= 75,000/mcL

- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert?s syndrome
(< 5 if metastatic involvement of the liver)

- Serum lipase =< 1.5 x ULN

- Serum amylase =< 1.5 x ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN

- Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram or multi-gated
acquisition (MUGA)

- Normal QT interval on screening electrocardiogram (ECG), defined as QT interval
corrected of =< 450 ms in males or =< 470 ms in females

- Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault
formula) >= 60 mL/min OR 24-hour urine creatinine clearance >= 60 mL/min

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients with hematological malignancies

- Patients with ALK positive (+) lung cancer

- Major surgery (e.g. thoracic, abdominal, vascular, neurosurgery) within 30 days prior
to registration on study

- Pregnant women or mothers who are breastfeeding

- Patients who are incarcerated

- Patients who have a history or the presence at baseline of pulmonary interstitial
disease or drug-related pneumonitis, or radiation pneumonitis

- Patients who have a known history of human immunodeficiency virus (HIV); testing not
required in the absence of history

- Patients with history of clinically significant bleeding disorder or history of active
significant gastrointestinal (GI) bleeding within 3 months of first dose of brigatinib

- Patients who have malabsorption syndrome or other GI illness or condition that could
affect oral absorption of the study drug

- History of allergic or suspected hypersensitivity reactions attributed to compounds of
similar chemical or biologic composition to brigatinib

- Patients with history of clinically significant atrial arrhythmias (requiring any
anti-arrhythmic therapy or as determined by the treating physician) or any history of
ventricular arrhythmias

- Patients who have significant, uncontrolled or active cardiovascular disease,
including but not restricted to the following:

- Myocardial infarction (MI) within 6 months prior to first dose of brigatinib

- Unstable angina (UA) within 6 months prior to first use

- Decompensated congestive heart failure within 6 months prior to first dose

- Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months
prior to first dose

- Clinically significant, uncontrolled intercurrent illness including, but not limited
to:

- Symptomatic or active infection requiring intravenous (IV) antibiotics

- Psychiatric illness and/or social situations that would limit compliance with
completion of study requirements

- Patients on medications known to be associated with torsades de pointes

- Patients who have uncontrolled hypertension; patients with hypertension should be
under treatment on study entry to control blood pressure

- Patients who have received cytotoxic chemotherapy, investigational agents, or
radiation within 14 days, except stereotactic radiosurgery (SRS) or stereotactic body
radiosurgery

- Patients who have received monoclonal antibodies or had major surgery within 30 days
of the first dose of brigatinib

- Patients who have not recovered (=< Common Terminology Criteria for Adverse Events
[CTCAE] grade 1) from adverse events (with the exception of alopecia) due to agents
administered more than 4 weeks earlier

- Patients with symptomatic CNS metastases that are neurologically unstable or require
increasing dose of corticosteroids

- Patients with current spinal cord compression