Hippocampal Avoidance in Craniospinal Irradiation for the Treatment of Leptomeningeal Metastases From Breast Cancer or Non-small Cell Lung Cancer

A Multi-Center Phase 2 Study of Hippocampal Avoidance in Craniospinal Irradiation for Leptomeningeal Metastases From Solid Tumors

This phase II clinical trial studies how well craniospinal irradiation (CSI) with hippocampal avoidance, using proton therapy or volumetric modulated arc therapy (VMAT), works in treating patients with breast cancer or non-small cell lung cancer (NSCLC) that has spread from the original (primary) tumor to the cerebrospinal fluid (CSF) and meninges (thin layers of tissue that cover and protect the brain and spinal cord) (leptomeningeal metastases). Radiation therapy is an effective treatment in relieving localized symptoms caused by leptomeningeal metastases. However, the type of radiation therapy typically used does not prevent the spread of leptomeningeal disease. CSI (radiation therapy directed at the brain and spinal cord to kill tumor cells) may be able to target all of the areas of possible leptomeningeal tumor spread. CSI may however result in significant neurological side effects due to radiation damage to a part of the brain called the hippocampus. Hippocampal avoidance (HA) reduces the amount of radiation to the hippocampus. Proton or VMAT CSI with HA may be an effective treatment while reducing neurological side effects for patients with leptomeningeal metastases from breast cancer and NSCLC.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Lung Non-Small Cell Carcinoma; Anatomic Stage IV Breast Cancer AJCC v8; Stage IV Lung Cancer AJCC v8; Metastatic Breast Carcinoma; Metastatic Malignant Neoplasm in the Leptomeninges
• Intervention / Treatment: Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Other: Survey Administration; Procedure: Positron Emission Tomography; Other: Electronic Health Record Review; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Radiation: Proton Beam Craniospinal Irradiation; Radiation: Volume Modulated Arc Therapy; Procedure: Hippocampal-Avoidance Craniospinal Irradiation

Detailed Description

OUTLINE:

Patients undergo proton or photon VMAT CSI with HA over approximately 45 minutes once daily (QD) for 10 days (Monday-Friday) in the absence of unacceptable toxicity. Patients may also undergo computed tomography (CT) or positron emission tomography (PET)/CT during screening. Additionally, patients will undergo additional CT for radiation planning during screening and magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection at the discretion of the treating physician and principal investigator throughout the study.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, and then at the time of CNS disease progression, up to 1 year.

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lia M. Halasz; Phone Number: 206-897-2121; Email: lhalasz@uw.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Not yet recruiting
      • University of California San Francisco
      • Principal Investigator: Steve Braunstein
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
      • Principal Investigator: Jonathan Yang
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Principal Investigator: Lia M. Halasz
      • Contact: Lia M. Halasz; Phone Number: 206-897-2121; Email: lhalasz@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with breast cancer or NSCLC malignancies with leptomeningeal metastases established radiographically and/or through CSF cytology
• Patients who are candidates for radiation therapy for the treatment of leptomeningeal metastases
• Patients ≥ 18 years old
• Karnofsky performance status (KPS) ≥ 60 or Eastern Cooperative Oncology Group (ECOG) ≥ 2
• The patient is able to provide informed consent
• Hemoglobin > 8 g/dL
• Absolute neutrophil count > 1,000/mm
• Platelet count > 100,000/mm
• Participants born female at birth must either be of non-reproductive potential (i.e. post-menopausal by history [≥ 60 years old, or with no menses for > 1 year without an alternative medical cause], OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum /urine pregnancy test within 3 weeks prior to starting radiation therapy (RT)
• Patients with reproductive potential must agree to practice two highly effective contraceptive methods

Exclusion Criteria:

• Patients with multiple, serious major neurologic deficits per physician/investigator assessment including encephalopathy
• Patients with extensive systemic disease and without reasonable systemic treatment options
• Patients who are unable to undergo MRI brain and spine with gadolinium contrast
• Previous radiotherapy to the intended treatment site that precludes developing a treatment plan that respects normal tissue tolerances
• Gross ventricular disease
• Brain metastases within 5 mm of the hippocampal contours not previously treated
• Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (Proton or Photon VMAT CSI); Patients undergo proton or photon VMAT CSI with HA over approximately 45 minutes once daily (QD) for 10 days (Monday-Friday) in the absence of unacceptable toxicity. Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT during screening. Additionally, patients undergo additional CT for radiation planning during screening and magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection at the discretion of the treating physician and principal investigator throughout the study.

Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Other: Survey Administration; Ancillary studies; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Other: Electronic Health Record Review; Ancillary studies; Procedure: Computed Tomography; Undergo PET/CT and/or CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biospecimen Collection; Undergo CSF sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Radiation: Proton Beam Craniospinal Irradiation; Undergo proton CSI; Other Names: Craniospinal Proton Beam Radiation Therapy; p-CSI; Proton Craniospinal Irradiation; Proton Craniospinal Radiation Therapy; Radiation: Volume Modulated Arc Therapy; Undergo photon VMAT CSI; Other Names: VMAT; Volumetric Modulated Arc Therapy (procedure); Procedure: Hippocampal-Avoidance Craniospinal Irradiation; Undergo HA; Other Names: Hippocampal-sparing Craniospinal Irradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central nervous system (CNS)-progression free survival (PFS)	PFS is defined as time from craniospinal irradiation (CSI) to CNS disease progression or death. CNS-PFS will be summarized using Kaplan-Meier methodology. Median, 95% confidence interval (CI) and Kaplan-Meier plot will be provided. One-sample log-rank test will be used to test if the median CNS PFS of hippocampal avoidance in CSI for leptomeningeal metastases from breast cancer or non-small cell lung cancer (NSCLC) is significantly larger than the expected median CNS PFS with involved-field radiation therapy (IFRT), i.e., 2.5 months. P-value will be provided.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of adverse events associated with hippocampal avoidance craniospinal irradiation (HA-CSI)	The analyses of the adverse events associated with HA-CSI will be descriptive in nature. Summary tables and listings will be provided for all reported adverse events (AEs).	Up to 12 months
Overall survival (OS)	Comparison of OS between the study group and the historical cohort will be analyzed using stratified log-rank test. OS will be estimated and visualized using Kaplan-Meier methods.	Up to 12 months
Neurocognitive function assessment	Linear mixed models will be used to examine changes in neurocognitive domain (attention, executive functions, memory) performances from pre-RT baseline to 3, 6, and 12 months. Magnitude of change will be examined at each timepoint using standardized effect sizes (e.g., Cohen's d). For each timepoint, the study investigators will examine the proportion of individuals who demonstrate a reliable change in at least 2 (out of 10) test performances as compared to pre-RT baseline performances.	Up to 12 months

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Lia M. Halasz, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: July 18, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): August 14, 2026
• Last Update Submitted That Met QC Criteria: August 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Skin Diseases; Breast Diseases; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Meningeal Neoplasms; Central Nervous System Neoplasms; Skin and Connective Tissue Diseases; Lung Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Meningeal Carcinomatosis; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Biopsy; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Diagnostic Techniques, Neurological; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Specimen Handling; Magnetic Resonance Spectroscopy; Spinal Puncture; Radiotherapy, Intensity-Modulated
• Other Study ID Numbers: RG1124476; NCI-2024-05661 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0020569 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes