ARRY-380 + Trastuzuamab for Breast w/ Brain Mets

If a patient participates in this research study, the patient will receive ARRY-380 and a
drug-dosing diary to record when the patient took ARRY-380 for each study treatment cycle.
Each study treatment cycle will last for 3 weeks (21 days) during which time the patient will
be taking ARRY-380 by mouth every day. At the time the patient enters the study, the patient
will be assigned to either Arm A or Arm B. The difference between the two study arms includes
ARRY-380 administered twice-daily (morning and evenings - Arm A) or once-daily (morning - Arm
B). The patient will also be given Trastuzumab by intravenous infusion (by vein) on day 1 of
each cycle (same dose and schedule for both study arms).

The dose of trastuzumab will be the same for everyone on study, and will be the standard
approved dose for this medication. In the first portion of the study, the investigators will
examine the effects of different dose of ARRY-380 when given in combination with trastuzumab.
Initially, 3 participants will be treated with a low dose of the ARRY-380 in combination with
standard dose of trastuzumab. If this dose does not cause intolerable side effects, more
participants may receive the drug combination at the same dose. The patient will be informed
of the assigned dose when the patient enters the study. The patient will be asked to take
ARRY-380 for as long as the study treatment is of possible benefit to the patient. After the
patient is finished taking ARRY-380, the study doctor will ask the patient to visit the
office for follow-up exams for at least one more visit within 4 weeks of the patient's last
study treatment.

At the start of each cycle the patient will have:

- A medical history, which includes questions about health, current medications, and any
allergies.

- Performance status, which evaluates the ability to carry on with usual activities.

- Physical examination, the doctor will examine the patient body, including measuring
height, weight, and vital signs (blood pressure, body temperature, pulse rate and
breathing rate).

- A neurological examination to asses any neurological symptoms(for example, difficulties
with balance)

- Blood tests will be drawn at the beginning of each study treatment cycle for tests to
monitor the function of liver and kidneys and to check blood cell counts. In addition,
blood tests will be drawn on days 4, 8, and 15 of the first cycle of study treatment to
monitor liver function.

Periodically the patient will undergo:

- The patient will have a brain MRI every two cycles. If the brain scans are stable or
improved after the patient has been on the study for 6 months or longer, the frequency
of your body scans will be decreased to once every 4 cycles. The patient will also have
CT or MRI scans of the body at the end of cycle 2, cycle 4 and every 4 cycles
thereafter. The research doctor may ask the patient to have a bone scan at the same time
points if this is clinically indicated.

- Electrocardiogram (EKG), which shows the electrical activity of the heart. It will be
performed on Day 1 of cycle 2.

- Echocardiogram (ECHO) (ultrasound of the heart) or MUGA scan (test of heart function
using a small amount of a radioactive substance). This will be performed every 3-4
months.

Additional research procedures to be performed:

- On Cycle 1, Day 15 blood for ("PK") pharmacokinetic (what the body does to the drug)
sampling will be drawn before the morning dose of ARRY-380, after 2 hours and after six
hours.

- Blood tests for research, which will include about 2 tablespoons of blood collected
before cycle 1 and after coming off study treatment. In general terms, scientists will
study the genes, the RNA, and the proteins that are found in the blood samples.
Scientists will also measure and characterize circulating tumor cells in the blood, if
they are present. In addition, these specimens may be tested with new types of tests, as
they become available. Results of the research tests on blood will not be reported back
to the patient.

- Archival Tumor Tissue Sample: A sample (or samples) of the patient's tumor tissue (from
a past surgery and/or biopsy) will be collected and used to learn more about the
development of metastatic breast cancer. In general terms, scientists will study the
genes, the RNA, and the proteins that are found both in breast tumors and in normal
tissue. In addition, these specimens may be tested with new types of tests, as they
become available. Laboratory-based investigators conducting this research will not have
access to patient identification information such as name or medical record number.
Results of the research tests on tissue will not be reported back to the patient.

After the final dose of the study drug:

The patient will have a follow-up visit one month after coming off study treatment. During
that visit, the patient will have a physical examination, functional assessment, assessment
of any toxicities and current medications. If the patient continues to have ongoing side
effects related to the study treatment, the investigators will continue to follow the patient
until these side effects resolve. If the patient withdrew from the study for another reason
other than tumor progression, the patient will continue to be followed until tumor
progression.

Planned Follow-up:

The investigators would like to keep track of the patient's medical condition indefinitely.
The investigators would like to do this either by seeing the patient in clinic or by
contacting the patient and the patient's primary doctor periodically to see how the patient
is doing. Keeping in touch with the patient and checking the patient's condition periodically
helps the investigators look at the long-term effects of the research study.

Inclusion Criteria:

- Participants must meet the following criteria on screening examination to be eligible
to participate in the study. Laboratory evaluations must have been performed within 14
days of study entry. Non-laboratory tests must have been performed within 30 days of
study entry. Evaluation of LVEF must have been performed within 60 days of study
entry:

- Participants must have histologically confirmed HER2+ (3+ by immunohistochemistry
and/or FISH ratio >/= 2.0) invasive breast cancer. Central confirmation of HER2 status
is not required.

- Participants must have measurable CNS disease, defined as at least one parenchymal
brain lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded) as > 10 mm by local radiology review (note: measurable
non-CNS disease is NOT required for study participation). See section 10 for the
evaluation of measureable disease.

- New or progressive CNS lesions, as assessed by the patient's treating physician.

- It is anticipated that some participants may have multiple progressive CNS lesions,
one or several of which are treated with SRS or surgery with residual un-treated
lesions remaining. Such participants are eligible for enrollment on this study
providing that at least one untreated lesion is measurable, as defined in section
3.1.2. The location of the measurable lesion should be documented in the patient chart
and case report form.

- Participants who have had prior cranial surgery are eligible, provided that there is
evidence of measurable residual or progressive lesions. If a patient has surgical
resection followed by WBRT, then there must be evidence of progressive CNS disease
after the completion of WBRT.

- Participants who have had prior WBRT and/or SRS and then whose lesions have progressed
thereafter are also eligible. In this case, lesions which have been treated with SRS
may be considered as target lesions if there is unequivocal evidence, in the opinion
of the treating physician, of progression following SRS.

- Participants who have not previously been treated with cranial radiation (e.g. WBRT or
SRS) are eligible to enter the study, but such participants must be asymptomatic from
their CNS metastases and not requiring corticosteroids.

- No increase in corticosteroid dose in the week prior to the baseline brain MRI.

- Age ≥18 years

- ECOG performance status 0 to 2 (see Appendix A)

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,000/mcL

- Platelets ≥ 75,000/mcL

- Total bilirubin < 2 X institutional upper limit of normal

- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal in participants
without liver metastases and < 5 ULN in participants with documented liver metastases

- Left ventricular ejection fraction ≥ 50%, as determined by RVG or echocardiogram
within 60 days prior to initiation of protocol therapy

- Prior therapy - Prior trastuzumab and/or lapatinib are allowed. There is no limit on
the number of prior lines of therapy.

- The effects of ARRY-380 on the developing human fetus are unknown. For this reason and
because other therapeutic agents used in this trial may be teratogenic, 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 for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

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

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.

- Participants who have had chemotherapy or radiotherapy within 14 days prior to
entering the study (with the exception of trastuzumab) or those who have not recovered
from adverse events to ≤ grade 1 due to agents administered more than 4 weeks earlier.

- Participants may not be receiving any other investigational agents. Concurrent
treatment with bisphosphonates or denosumab is allowed

- History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical
or biologic composition to ARRY-380 or trastuzumab

- Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker,
shrapnel, or ocular foreign body

- Leptomeningeal carcinomatosis as the only site of CNS involvement

- More than 2 seizures over the last 4 weeks prior to study entry

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnancy (positive pregnancy test) or lactation

- Individuals with a history of a different active malignancy are ineligible.
Participants with a history of other malignancies are eligible if they have been
disease-free for at least 2 years, not on active treatment, and deemed by the
investigator to be at low risk for recurrence of that malignancy. Individuals with the
following cancers are eligible if diagnosed and treated within the past 2 years:
cervical cancer in situ, basal cell or squamous cell carcinoma of the skin.