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

Phase 2

Not yet recruiting

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

• Registration Number: NCT06518057
• Lead Sponsor: University of Washington

Brief Summary

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.

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. They will undergo additional CT for radiation planning during screening and magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2024-07-18
• Study First Submitted QC: 2024-07-18
• Study First Posted: 2024-07-24
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-20
• Last Update Posted: 2024-12-27
• Study Start: 2025-02-01
• Primary Completion: 2026-06-30
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 22

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
• 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 pregnancy test within 2 weeks prior to starting treatment
• Patients with reproductive potential must agree to practice an effective contraceptive method

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (Proton or Photon VMAT CSI)	Computed Tomography	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Proton Beam Craniospinal Irradiation	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Magnetic Resonance Imaging	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Electronic Health Record Review	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Positron Emission Tomography	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Survey Administration	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Biospecimen Collection	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Lumbar Puncture	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.
Treatment (Proton or Photon VMAT CSI)	Volume Modulated Arc Therapy	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, as well as additional CT for radiation planning during screening. Additionally, patients undergo magnetic resonance imaging (MRI) throughout the trial. They may also undergo lumbar puncture (LP) or alternative methods for cerebral spinal fluid (CSF) collection.

Primary Outcome Measures

Name	Time	Method
Central nervous system (CNS)-progression free survival (PFS)	Up to 12 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of adverse events associated with hippocampal avoidance craniospinal irradiation (HA-CSI)	Up to 12 months	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).
Neurocognitive function assessment	Up to 12 months	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.
Overall survival (OS)	Up to 12 months	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.

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States