A Phase II Study of Dacomitinib in Progressive Brain Metastases

The purpose of this study is to investigate the use of the irreversible pan-ErB kinase
inhibitor dacomitinib in the treatment of brain metastases, as measured by radiographic
objective response rate.

The rationale of this study is three-fold. First, the use of dacomitinib, an irreversible
pan-ErB kinase inhibitor, is to improve the duration of response seen by reversible, EGFR
only inhibitors. Inhibition of the multiple ErB kinases may interfere with receptor
cross-talk as a method of developing resistance; indeed, patients who have failed erlotinib
treatment for systemic disease have seen responses to dacomitinib. The second rationale is
to evaluate the pharmacokinetics of the penetration of dacomitinib into the CSF to determine
if adequate drug levels reach the CNS, and determine if the current dosing regimen is
appropriate. The third rationale is to determine if specific molecular phenotypes
preferentially respond to dacomitinib. As part of this study, serum and cerebrospinal fluid
will be collected and analyzed both for drug levels and for molecular markers to key
elements of the ErB signaling cascade. The objective of the marker analysis to identify a
distinct molecular phenotype that may preferentially respond to targeted drug therapy in the
future.

Inclusion Criteria:

- Pathologically (histologically or cytologically) documented extracranial diagnosis of
primary lung cancer, melanoma, human epidermal growth factor receptor 2
(HER2)-amplified breast cancer, or HER2-amplified gastric cancer, with brain
metastasis detected by contrast enhanced MRI or CT is required. Patients with
concurrent leptomeningeal diseases are eligible.

- Has progression and measureable brain disease in the brain by magnetic resonance
imaging (MRI) or computed tomography (CT).

- Has stable, or no evidence of, extracranial disease and not receiving systemic
therapy for extracranial disease.

Note: Patients with stable disease must have already received standard therapy or are
intolerant to standard therapy.

- Prior therapy for brain metastasis is not required; patients may either have refused
radiation therapy or have received prior radiation therapy. Patients having received
prior standard whole brain radiation therapy (WBRT) or stereotactic radiosurgery
(SRS) must have completed treatment greater than 4 weeks prior to study initiation.

- Has recovered from the toxic effects of prior therapy to Common Toxicity Criteria for
Adverse Effects (CTCAE) Grade 1 or to their clinical baseline.

- Age ≥18.

- Life expectancy > 3 months in the opinion of the investigator.

- KPS ≥ 60%.

- Adequate organ and marrow function.

Exclusion Criteria:

- Current or planned use of systemic therapy for extracranial primary tumor.

- Current or anticipated use of other investigational agents.

- Presence of uncontrolled seizures ≤ 5 days prior first drug dose, defined as status
epilepticus or multiple seizures not responding to appropriate therapy.

- Current or anticipated use of enzyme-inducing anti-epileptic drugs

- Insufficient time for recovery from prior therapy: less than 28 days from WBRT or
SRS; less than 28 days from any investigational agent; less than 28 days from prior
cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine,
42 days from nitrosoureas, 21 days from procarbazine administration), and less than 7
days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic
acid, etc. When radiation necrosis is suspected, confirmatory imaging will be
performed, and patients with findings consistent with radiation necrosis will be
excluded.

- Current use or anticipated need for treatment with Coumadin® or other agents
containing warfarin (except low dose Coumadin (1 mg or less daily) administered
prophylactically for maintenance of in-dwelling lines or ports). Heparin, low
molecular weight heparin (LWMH), direct thrombin inhibitors and factor Xa inhibitors
are allowed. Rivaroxaban should be used with caution. Antiplatelet agents are
allowed.

- Current or anticipated need for treatment with drugs that are known substrates of
CYP2D6

- Current or anticipated need for treatment with proton pump inhibitors. Patients on
proton pump inhibitors who can be switched to H2-blockers before the start of the
study are still eligible.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dacomitinib.

- Known severe and/or uncontrolled medical disorder that would impair ability to
receive study treatment (i.e., uncontrolled diabetes, chronic renal disease, chronic
pulmonary disease, HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), or active
infection).

- Impaired cardiac function including any of the following: Congenital long QT syndrome
or a known family history of long QT syndrome; corrected QT interval (QTc) > 450
msec; history or presence of clinically significant ventricular or atrial
tachyarrhythmias; clinically significant resting bradycardia (< 50 beats per minute);
myocardial infarction within 1 year of starting study drug; other clinically
significant heart disease (e.g., unstable angina, congestive heart failure, or
uncontrolled hypertension)

- Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants.