An official website of the United States government
Government Funding Lapse Because of a lapse in government funding, the information on this website may not be up to date, transactions submitted via the website may not be processed, and the agency may not be able to respond to inquiries until appropriations are enacted.
The NIH Clinical Center (the research hospital of NIH) is open. For more details about its operating status, please visit cc.nih.gov.
Updates regarding government operating status and resumption of normal operations can be found at opm.gov.
Radiation Therapy Followed by Trastuzumab and Pertuzumab for the Treatment of HER2 Positive Breast Cancer that has Spread to the Leptomeninges
Trial Status: active
This phase I/II trial studies the side effects and best dose of pertuzumab when given together with trastuzumab after radiation therapy and to see how well it works in treating patients with HER2 positive breast cancer that has spread to the leptomeninges. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Pertuzumab and trastuzumab are called targeted therapies because they work by attaching themselves to specific receptors on the surface of breast tumor cells, known as HER2 receptors. HER2 receptors can be found on normal cells, but can also be found in larger numbers on some tumor cells. When these targeted therapies attach to HER2 receptors, cell growth signals within the cell are blocked and the tumor cell may be marked for destruction by the immune system. This process allows pertuzumab and trastuzumab to help slow or stop the growth of breast cancer. Pertuzumab and trastuzumab target different areas on the HER2 receptor, so they are believed to work together more effectively when combined after radiation therapy. Giving pertuzumab and trastuzumab after radiation therapy may help treat patients with HER2 positive breast cancer that has spread to the leptomeninges.
Inclusion Criteria
Confirmation of HER2 positivity
* All patients with HER2+ cancers will be allowed to enroll if they have LMD. Patients may be immunohistochemistry (IHC) 3+ and/or fluorescence in situ hybridization (FISH)-positive. IHC 2+ HER2 patients are eligible with reflex FISH-positive testing with the ratio >= 2.0
* And/or patients with HER2 positive cells in the CSF
Patients may have concomitant brain metastases
CSF sampling is required to document LMD if not documented by magnetic resonance imaging (MRI). Patients are still eligible if CSF is negative but LMD disease is documented on MRI
Life expectancy > 8 weeks
Consent to pretreatment tumor biopsy or retrieval of archival tissue
Creatinine < 1.5 x upper limit of normal (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 >= 2.5
Neutrophils >= 1000
Platelets >= 75,000
Hemoglobin >= 8
Left ventricular ejection fraction (LVEF) > 50%
Karnofsky performance status (KPS) >= 60
Age >= 18 years
Patients with surgery within 14 days 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 a 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. Contraception methods should start a minimum of 14 days before the first administration of the study drug and continue for the duration of study treatment and for at least 7 months after the last dose of the study treatment
Ability to sign an informed consent form. Informed consent must be given before study enrollment
Patients may continue treatment with intravenous (IV) trastuzumab, pertuzumab, or other HER2-directed, hormonal, or chemotherapeutic agents if controlling systemic disease and leptomeningeal metastases that developed while on these therapies. In addition, at time of systemic progression, patients may start additional agents at the discretion of the treating physician according to criteria
Exclusion Criteria
Current or prior participation in a study of an investigational agent or investigational 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 they develop or have progressive or persistent leptomeningeal metastases while on these agent(s)
Major surgery or significant traumatic injury that has not been recovered from 14 days 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 brain radiotherapy (WBRT) is not allowed while patients receive IT trastuzumab/pertuzumab; however, focal stereotactic or palliative radiation therapy (RT) is allowed
Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol
Additional locations may be listed on ClinicalTrials.gov for NCT04588545.
I. To determine the safety and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of intrathecal (IT) pertuzumab in combination with IT trastuzumab in the management of HER2+ breast leptomeningeal disease (LMD). (Phase I)
II. To evaluate OS following IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase II)
SECONDARY OBJECTIVES:
I. To define the cerebrospinal fluid (CSF) pharmacokinetics (PK) of IT trastuzumab/pertuzumab. (Phase I)
II. To evaluate the response rate (leptomeningeal and parenchymal) of IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase I)
III. To evaluate progression-free survival (PFS) (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase I)
IV. To evaluate OS following IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase I)
V. To evaluate PFS (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase II)
VI. To evaluate the 6-month and median overall survival following IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase II)
VII. Determine response rate (leptomeningeal and parenchymal) of IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. (Phase II)
TERTIARY OBJECTIVE:
I. To characterize CSF circulating tumor cells (CTCs) at baseline, changes that occur over the treatment period, and correlations with response to treatment. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of pertuzumab followed by a phase II study.
Patients undergo radiation therapy at the discretion of the treating radiation oncologist. Beginning at least 7 days after completion of radiation therapy, patients receive pertuzumab IT over 2-5 minutes and trastuzumab IT over 2-5 minutes twice weekly (BIW) during cycle 1, once weekly (QW) during cycle 2, and then every 2 weeks for subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 2 months thereafter.
