Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer

Intrathecal administration of pertuzumab and trastuzumab will occur via lumbar puncture
under fluoroscopic guidance by interventional radiology at Duke University Medical Center.
If pharmacokinetics are needed during the lumbar puncture at that cycle, 3 mL of CSF will be
collected (a minimum of 2 mL of CSF is needed for PK testing). If pharmacokinetics are not
needed during the lumbar puncture at that cycle, 3 mL of CSF will be removed to allow for
injection of an equivalent volume of intrathecal therapy. Once the CSF is removed, the
intrathecal pertuzumab and trastuzumab will be administered using aseptic technique.

Patients will be treated using a 3+3 dose-escalation design. Patients will not be accrued to
the next cohort (dose escalation) until at least one patient on the previous cohort has been
followed for six weeks. If a dose limiting toxicity (DLT) is seen in a patient then the
cohort will be expanded by an additional 3 patients to allow for 1 in 6 patients per cohort
to have a DLT before dose escalation. Dose limiting toxicity will be assessed weekly during
the first six weeks of the treatment.

Patients will be treated weekly for the first six weeks and then every 3 weeks (q21 days).
Once the maximum tolerated dose is reached, an additional 12 patients will be enrolled in
the cohort at the maximum tolerated dose. The maximum number of enrolled patients is 36.
Dosing is as follows: Cohort 1 - 80mg IT trastuzumab, 10mg IT pertuzumab, cohort 2 - 80mg IT
trastuzumab, 20mg IT pertuzumab, cohort 3 - 80mg IT trastuzumab, 40mg IT pertuzumab, cohort
4 - 80mg IT trastuzumab, 80mg IT pertuzumab. If the lowest dose level is found to be too
toxic, the trial will stop without finding a maximum tolerated dose.

Inclusion Criteria:

- HER2 positive by 2013 ASCO-CAP guidelines (IHC 3+ and/or FISH positive; IHC 2+ HER2
patients are eligible with reflex FISH positive testing with the ratio ≥ 2.0) breast
cancer patients with single untreated asymptomatic or minimally symptomatic brain
metastasis by MRI.

- Patients can have previous brain metastasis that was completely surgically resected
if the previously resected lesion is at least 1 cm from target lesion(s) for this
study. The location of the previous resection cavity is determined by the
post-resection MRI.

- Patients can have previous brain metastasis that was treated with stereotactic
radiosurgery (SRS) if the previously treated lesion is at least 1cm from the target
lesion(s) for this study. The location of the previous SRS treatment location is
determined by the SRS MRI.

- Patients can be on steroids as long as the dose has been stable for ≥ 7 days

- No limitations on prior systemic or intrathecal therapies.

- There are no restrictions on systemic therapy at enrollment. For further details
regarding systemic therapy, see the "Concurrent Systemic Therapy" section in 5.0.

- Women of childbearing potential must commit to contraceptive use while enrolled on
the trial and continue using contraceptive for at least 7 months post study drug
administration.

- Life expectancy > 8 weeks

- Laboratory criteria: normal renal function: creatinine < 1.5 x upper limit of normal
(ULN)), liver function: bilirubin < 1.5 x ULN, transaminases < 2 x ULN, except in
known hepatic disease, wherein may be < 5 x ULN, and blood counts: WBC ≥ 2.0,
Neutrophils ≥1500, platelets ≥100,000, Hemoglobin ≥ 10.

- LVEF (left ventricular ejection fraction) ≥ 50%

- Karnofsky performance status (KPS) > 50

- Age > 18 years

- Patients must have the ability to give informed consent.

- Patients must have a signed informed consent form prior to enrollment on study.

- Negative serum pregnancy test for pre-menopausal women and women within 12 months
from the onset of menopause.

Exclusion Criteria:

- No seizures, focal weakness of any extremity (by neurologic exam), or stroke symptoms
in the past month.

- No history of prior whole brain radiation.

- No history of lumbar surgery or other pre-existing spinal conditions that would
preclude frequent, safe, reliable lumbar punctures.

- No history of serious cardiac arrhythmia or EF < 50%.

- Systemic sites of disease need to be stable on systemic therapy based on the most
recent (within 12 weeks) staging scans.

- Radiation while on study is not allowed EXCEPT to a localized region for pain
control.

- No history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ
of the cervix) unless the patient has been in remission and off all other cancer
therapy for at least 3 years.

- Patients should have no significant psychiatric illness or medical illness that would
preclude the ability to comply with the protocol.

- Patients may not be pregnant or breastfeeding.

- No known hypersensitivity to trastuzumab or pertuzumab.

- Symptomatic intrinsic lung disease or extensive tumor involvement in the lungs
resulting in dyspnea at rest.