Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in HER2+ Breast Leptomeningeal Disease

Inclusion Criteria:

• Confirmation of HER2 positivity. All patients with HER2+ cancers will be allowed toenroll if they have leptomeningeal disease (LMD). Patients may be IHC 3+ and/orFISH-positive. IHC 2+ HER2 patients are eligible with reflex FISH-positive testingwith the ratio ≥2.0.

And/or patients with HER2 positive cells in the cerebral spinal fluid.

• Participants may have concomitant brain metastases

• Cerebrospinal fluid (CSF) sampling is required to document LMD if not documented byMRI. Participants are still eligible CSF is negative but LMD disease is documentedon MRI

• Life expectancy greater than 8 weeks

• Consent to pretreatment tumor biopsy or retrieval of archival tissue

• Normal renal (creatinine <1.5 × upper limit of normal [ULN]), liver (bilirubin < 1.5 × ULN, transaminases <3.0 × ULN, except in known hepatic disease, wherein may be <5 × ULN) and blood counts (white blood cells ≥2.5, neutrophils ≥1000, platelets ≥75,000, hemoglobin ≥8)

• LVEF >50%

• KPS >/= 60

• Patients with surgery within 14 days should have recovered from all effects of thesurgery and be cleared by their surgeon

• There is no limit on prior systemic or IT therapies

• Must be willing to have an Ommaya reservoir placed and a candidate for an Ommayareservoir placement

• Women of childbearing potential and sexually active males must commit to the use ofeffective contraception while on study. Contraception methods should start a minimumof 14 days before the first administration of study drug and continue for theduration of study treatment and for at least 7 months after the last dose of studytreatment.

• Ability to sign informed consent.

• Patients may continue treatment with IV trastuzumab, pertuzumab, or otherHER2-directed, hormonal, or chemotherapeutic agents if controlling systemic diseaseand leptomeningeal metastases that developed while on these therapies. In addition,at time of systemic progression, patients may start additional agents at thediscretion of the treating physician according to criteria per protocol.

Exclusion Criteria:

• Current or prior participation in a study of an investigational agent orinvestigational device within 2 weeks of the first dose of study treatment

• Cannot be on systemic agents (chemotherapy) that have Central Nervous System (CNS)penetration (temozolomide, carmustine, lomustine, etoposide, capecitabine,carboplatin, vinorelbine, bevacizumab, irinotecan, and topotecan) unless theydevelop or have progressive or persistent leptomeningeal metastases while on theseagent(s). See protocol for additional information regarding systemic therapies.

• Major surgery or significant traumatic injury that has not been recovered from 14days before the initiation of study drug

• Symptomatic lung disease resulting in shortness of breath at rest

• Women who are pregnant or breastfeeding

• History of serious adverse event to any of the study drugs or study drug components

• Whole Body Radiation Therapy (WBRT) is not allowed while patients receive ITtrastuzumab/pertuzumab; however, focal stereotactic or palliative RT is allowed

• Significant medical or psychiatric illness that would interfere with compliance andability to tolerate treatment as outlined in the protocol