Testing Proton Craniospinal Radiation Therapy Versus the Usual Radiation Therapy for Leptomeningeal Metastasis, RADIATE-LM Trial

Study Purpose

This phase III trial compares proton craniospinal irradiation (pCSI) to involved-field radiation therapy (IFRT) for the treatment of breast or non-small cell lung cancer that has spread from where it first started to the cerebrospinal fluid filled space that surrounds the brain and spinal cord (leptomeningeal metastasis). Patients with leptomeningeal metastasis (LM) may develop multiple areas of nervous system (neurologic) impairment that can be life-threatening. Radiation therapy (RT) effectively relieves local symptoms due to LM. RT uses high energy radiography (x-rays), particles, or radioactive seeds to kill cancer cells and shrink tumors. IFRT is commonly used to treat symptoms of LM. IFRT is radiation treatment that uses x-rays to treat specific areas of LM and to relieve and/or prevent symptoms. pCSI uses protons that can be directed with more accuracy than x-rays which allows treatment of the entire central nervous system space containing the cerebrospinal fluid (CSF), brain, and spinal cord. The pCSI treatment could delay the worsening of LM. Giving pCSI may be better than IFRT in treating LM in patients with breast or non-small cell lung cancer.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- PRIOR TO STEP 1 REGISTRATION.

- Patients with pathologically (histologically or cytologically) proven diagnosis of breast cancer or NSCLC.

- Patients must have newly diagnosed leptomeningeal metastasis established through at least one of the following: - Positive CSF cytology for malignancy.

- CSF cytology with suspicious cells is considered positive; CSF cytology with atypical cells is considered equivocal and not positive.

- Patients with an equivocal or negative CSF cytology result, or not suitable for CSF sampling, radiographic diagnosis of leptomeningeal metastasis with linear and/or nodular disease and documentation of typical clinical signs (European Association of Neuro-Oncology [EANO]-European Society for Medical Oncology [ESMO] Diagnostic Criteria Type IIA-IIC) is required.

- Patients with typical clinical signs of leptomeningeal metastasis may have one or more of the following symptoms and signs: headache, nausea, vomiting, mental status change, gait difficulty, cranial nerve palsy, diplopia, visual change, hearing loss, radicular weakness, radicular sensory change, urinary retention, saddle anesthesia, constipation, neck pain, and back pain.

- For patients with prior history of immunotherapy or current immunotherapy, CSF sampling rather than just MRI enhancement is strongly recommended to exclude immune-related aseptic meningitis.

- Patients must be candidates for radiation therapy for the treatment of leptomeningeal metastasis.

- Age ≥ 18.

- PRIOR TO STEP 2 REGISTRATION.

- Note: Step 2 registration must occur no later than 30 calendar days after step 1 registration.

- Financial clearance for proton therapy treatment.

- Patients must have systemic disease evaluation through standard of care imaging for example CT chest/abdomen/pelvis or body PET/CT.

- Karnofsky performance status ≥ 60.

- Not pregnant and not nursing.

- Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration.

Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.

- Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable) - Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (Note: the use of granulocyte-colony stimulating factor or other intervention to achieve ANC ≥ 1,000/mm^3 is acceptable) - Platelets ≥ 100,000/mm^3 (Note: the use of transfusion or other intervention to achieve platelets ≥ 100,000/mm^3 is acceptable) - Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (patients with known Gilbert disease without other clinically significant liver abnormalities are not excluded) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × ULN.

- No prior radiation therapy to the spinal cord with equivalent dose in 2 gray (Gy) fractions (EQD2) more than 40Gy or cauda equina with EQD2 more than 50Gy using alpha/beta ratio of 3.

- No prior treatment for leptomeningeal metastasis (note: prior CNS treatment for other non-leptomeningeal disease is allowed) - No history of unstable angina requiring hospitalization in the last 3 months.

- No history of myocardial infarction within the last 3 months.

- New York Heart Association Functional Classification II or better (New York Heart Association [NYHA] Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.

)

- No active infection currently requiring intravenous (IV) antibiotic management.

- No active chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy.

- No CTCAE v5.0 ≥ grade 2 encephalopathy

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06500481
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	NRG Oncology
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Jonathan T Yang
Principal Investigator Affiliation	NRG Oncology
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Leptomeninges, Stage IV Lung Cancer AJCC v8

Additional Details

PRIMARY OBJECTIVE:

I. To compare overall survival (OS) between proton craniospinal irradiation (pCSI) and involved-field radiotherapy (IFRT) in patients with breast cancer or non-small cell lung cancer (NSCLC) leptomeningeal metastasis.

SECONDARY OBJECTIVES:

I. To compare central nervous system progression-free survival (CNS PFS) between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis.

II. To compare time to CNS progression between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis.

III. To compare CNS PFS between pCSI and IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis, as evaluated by central review of imaging.

IV. To compare the rate of radiation-induced central nervous system necrosis between pCSI versus (vs.#46;) IFRT in patients with breast cancer or NSCLC leptomeningeal metastasis.

V. To characterize treatment-related adverse events using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

VI. To compare patient-reported outcomes (symptoms severity subscale per MD Anderson Symptom Inventory for Brain Tumors [MDASI-BT] and MD Anderson Symptom Inventory for Spine Tumors [MDASI-SP]) in patients with breast cancer or non-small cell lung cancer leptomeningeal metastasis.

EXPLORATORY OBJECTIVE:

I. To compare patient-reported outcomes (symptoms interference, brain tumor-specific, spine tumor-specific subscales per MDASI-BT and MDASI-SP) in patients with breast cancer or non-small cell lung cancer leptomeningeal metastasis.

OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients undergo involved-field radiation therapy delivered to specific areas of LM that are causing and/or may cause symptoms 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT during screening and magnetic resonance imaging (MRI) as well as possible lumbar puncture (LP) throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study. ARM 2: Patients undergo pCSI radiation therapy delivered to the entire space containing the CSF, brain, and spinal cord 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT during screening and MRI as well as possible LP throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study. After completion of study treatment, patients are followed every 3 months for 12 months, and then every 6 months for up to 3 years from end of RT.

Arms & Interventions

Arms

Active Comparator: Arm 1 (IFRT)

Patients undergo involved-field radiation therapy delivered to specific areas of LM that are causing and/or may cause symptoms 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT during screening and MRI as well as LP throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study.

Experimental: Arm 2 (pCSI)

Patients undergo pCSI radiation therapy delivered to the entire space containing the CSF, brain, and spinal cord 5 days a week for a total of 10 days of treatment in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT during screening and MRI as well as possible LP throughout the study. Patients may optionally undergo research blood sample and CSF collection throughout the study.

Interventions

Procedure: - Biospecimen Collection

Undergo blood and CSF sample collection

Procedure: - Computed Tomography

Undergo CT or PET/CT

Radiation: - Involved-Field Radiation Therapy

Undergo IFRT

Procedure: - Lumbar Puncture

Undergo LP

Procedure: - Magnetic Resonance Imaging

Undergo MRI

Procedure: - Positron Emission Tomography

Undergo PET/CT

Radiation: - Proton Beam Craniospinal Irradiation

Undergo pCSI

Other: - Quality-of-Life Assessment

Ancillary studies

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Little Rock 4119403, Arkansas 4099753

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Recruiting

Address

University of Arkansas for Medical Sciences

Little Rock 4119403, Arkansas 4099753, 72205

Site Contact

Site Public Contact

501-686-8274

UC San Diego Health System - Encinitas, Encinitas 5346646, California 5332921

Status

Recruiting

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UC San Diego Health System - Encinitas

Encinitas 5346646, California 5332921, 92024

Site Contact

Site Public Contact

760-536-7700

UC San Diego Moores Cancer Center, La Jolla 5363943, California 5332921

Status

Recruiting

Address

UC San Diego Moores Cancer Center

La Jolla 5363943, California 5332921, 92093

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