Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

Phase I: Patients will be treated in cohorts of 3-6 based on standard phase I dose escalation
parameters requiring 0/3 or 1/6 patients per cohort to have a DLT before dose escalation.
Dosing is as follows: Cohort 1-10 mg IT, cohort 2-20 mg IT, cohort 3-30 mg IT and cohort 4-40
mg IT. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and
then every 2 weeks. Toxicity for DLT will be assessed during first 4 weeks of treatment.
Phase II: Patients will be treated with the MTD or maximal defined dose. Patients will be
treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks.

Inclusion Criteria:

ELIGIBILITY CRITERIA

- HER2 positive (IHC 3+ and/or FISH positive) breast cancer patients with leptomeningeal
metastases by MRI or CSF (if MRI is negative).

o Review will be performed for cases not reviewed at Northwestern for confirmation,
but will not preclude patients from entering the trial (pathology report is sufficient
for registration).

- Patients can have concomitant brain metastases as long as they do not require active
treatment or have been treated.

- Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma
will be eligible for phase I

- Life expectancy > 8 weeks

- Normal renal (creatinine < 1.5 ULN), liver (bilirubin < 1.5 x ULN, transaminases < 3.0
x ULN, except in known hepatic metastasis, wherein may be < 5 x ULN) and blood counts
(WBC > 3.0, Neutrophils > 1500, platelets >100 000, Hemoglobin > 10).

- LVEF > 50%

- KPS > 50

- Age > 18 years

- Cannot be on systemic agents (chemotherapy) that have CNS penetration unless they
develop leptomeningeal metastases while on these agent(s) and have controlled systemic
disease. May continue on IV trastuzumab, lapatinib or hormonal agents if controlling
systemic disease and developed LM while on therapy. Patients requiring systemic
chemotherapy are eligible but will not be able to start treatment until after the
first assessment by imaging and cytology.

- Patients may need a CSF flow study at the discretion of the treating principal
investigator. If a spinal block is seen by CSF flow study or MRI, it will need local
RT prior to treatment. Concurrent radiation is not allowed.

- Patients should be > 2 weeks from RT treatment and all effects of treatment should
have resolved

- No limit on prior systemic or IT therapies.

- CSF sampling to document LM if not documented on MRI.

- Must be willing to have an Ommaya reservoir placed.

- NO history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ
of the cervix) unless in complete remission and off all therapy for the disease for a
minimum of 3 years.

- Significant medical or psychiatric illness that would interfere with compliance and
ability to tolerate treatment as outlined in the protocol.

- Women of childbearing potential and sexually active males must commit to the use of
effective contraception while on study.

- Women may not be pregnant or breast-feeding.

- Ability to sign an informed consent; can be signed by family member or health care
proxy. Informed consent must be done prior to registration on study.

- All patients must have given signed, informed consent prior to registration on study.

- No known hypersensitivity to trial medications Note: The eligibility criteria listed
above are interpreted literally and cannot be waived.

Exclusion Criteria:

- Any deviations from the inclusion criteria