Trastuzumab in Treating Leptomeningeal Metastases in Patients with HER2-Positive Cancer

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, TreatmentActive18 and overNU 10C03
NCI-2011-00110, STU00040150, STU00040150-MOD0003, NCT01325207

Trial Description


This phase I/II trial studies the side effects and best dose of trastuzumab and to see how well it works in treating cancer that has spread to the thin layers of tissue that cover and protect the brain and spinal cord (meninges) in patients with certain nervous system tumors or patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread.

Further Study Information


I. Determine the safety and the maximum tolerated dose (MTD) of intrathecal (IT) trastuzumab based on pre-defined dose levels. (Phase I)

II. Define the cerebrospinal fluid (CSF) pharmacokinetics (PK) of IT trastuzumab. (Phase I)

III. Determine response to IT trastuzumab: radiological, cytological and clinical. (Phase II)


I. Determine response to IT trastuzumab: radiological, cytological and clinical. (Phase I)


I. Determine the sensitivity and specificity of identification of CSF circulating tumor cells (CTC) at baseline in patients with leptomeningeal metastases (LM) from breast cancer. (Phase II)

II. Characterize CSF CTC baseline enumeration, and changes over time, and correlate with response to treatment. (Phase II)

III. Evaluate the feasibility of using CSF CTC for analysis of molecular characteristics and mutational status of LM, and comparison with primary cancer utilizing fluorescence in situ hybridization (FISH) and other methods of mutational analysis evaluation. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive trastuzumab IT twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months.

Eligibility Criteria

Inclusion Criteria:

Confirmation of HER2 positivity:

Phase I only: Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma will be eligible for phase I but are not required to have HER2 analysis; HER2 testing is only required for breast cancer patients with leptomeningeal metastases; HER2 positive (immunohistochemistry [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 leptomeningeal metastases by magnetic resonance imaging (MRI) or CSF (if MRI is negative) are eligible

Phase II only: ALL patients with HER2+ cancers of other histology will be allowed to enroll in phase II if they have leptomeningeal disease

NOTE: review will be performed for cases not reviewed at the participation institution for confirmation, but will not preclude patients from entering the trial (pathology report showing HER2 positivity is sufficient for registration)

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

Phase I/II: CSF sampling required to document LM if not documented by MRI; NOTE: patients are still eligible if CSF is negative but LM disease is documented on MRI

Life expectancy >= 8 weeks

Creatinine < 1.5 x upper limit of normal (or ULN)

Bilirubin =< 1.5 x ULN

Transaminases =< 3.0 x ULN, except in known hepatic disease, wherein may be =< 5 x ULN

White blood cells (WBC) >= 2.5

Neutrophils >= 1500

Platelets >= 75,000

Hemoglobin >= 9

Left ventricular ejection fraction (LVEF) > 45%

Karnofsky performance status (KPS) >= 50

Patients should be > 24 hours from radiation therapy (RT) treatment to areas of the neuro-axis and all effects of treatment should have resolved

Patients with a recent surgery should have recovered from all effects of the surgery 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 Ommaya reservoir placement

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

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

Exclusion Criteria:

Cannot be on systemic agents (chemotherapy) that have central nervous system (CNS) penetration (temozolomide, carmustine [BCNU], lomustine [CCNU], etoposide, Xeloda, carboplatin, Navelbine, bevacizumab, CPT-11 and topotecan; note: please check with study principal investigator [PI] [Dr. Raizer] to clarify other agents not listed) unless they develop or have progressive or persistent leptomeningeal metastases while on these agent(s) and have controlled systemic disease

NOTE: may continue on intravenous (IV) trastuzumab, pertuzumab, TDM-1, lapatinib or hormonal agents if controlling systemic disease and developed LM while on therapy

NOTE: patients requiring systemic agents (such as those listed above) are eligible but will not be able to start treatment until after the first assessment by imaging and cytology

Concurrent external beam radiation is not allowed with the exception of palliative radiotherapy to a localized region for pain control (i.e. vertebral disease, pelvis, etc) which IS allowed while on the study protocol

NOTE: 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

Patients who have controlled or responding leptomeningeal disease and develop brain metastases can remain on trial if their disease can be controlled with radiosurgery and does not require whole body radiation therapy (WBRT); NO history of any other concomitant 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

Patients should have NO significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol

Women may not be pregnant or breast-feeding

No known hypersensitivity to trastuzumab

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Northwestern University

  • National Cancer Institute
Jeffrey Joel Raizer, Principal Investigator

Trial Sites


Royal Oak

William Beaumont Hospital-Royal Oak

Padmaja Vani Venuturumilli
Ph: 248-551-6900

Padmaja Vani Venuturumilli
Principal Investigator


University of Washington Medical Center

Maciej Michal Mrugala
Ph: 206-616-8289

Maciej Michal Mrugala
Principal Investigator

Link to the current record.
NLM Identifier NCT01325207

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the record via the link above for more information about participating sites.