Clinical trial NCT06500481: Testing Proton Craniospinal Radiation Therapy Versus the Usual Radiation Therapy for Leptomeningeal Metastasis, RADIATE-LM Trial
Official title: A Phase III Randomized Clinical Trial of Proton Craniospinal Irradiation Versus Involved-Field Radiotherapy for Patients With Breast Cancer or Non-Small Cell Lung Cancer Leptomeningeal Metastasis (RADIATE-LM)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: 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
Lead sponsor: NRG Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2024-07-15
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.) 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.

Eligibility criteria: Inclusion Criteria:

* PRIOR TO STEP 1 REGISTRATION
* Patients with pathologically (histologically or cytologically) proven diagnosis of breast cancer or NSCLC. Patients must have systemic disease evaluation through standard of care imaging for example CT chest/abdomen/pelvis or body PET/CT
* 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 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 who are 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
* 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

Primary outcomes:
measure: Overall survival (OS)
timeFrame: From randomization until death due to any cause, assessed up to 3 years
Secondary outcomes:
measure: Central nervous system (CNS) progression-free survival (PFS)
timeFrame: Randomization until CNS progression or death, whichever occurs first, assessed up to 3 years
measure: Time to CNS progression
timeFrame: Randomization until CNS progression, assessed up to 3 years
measure: Time to radiation-induced CNS necrosis (TTRN)
timeFrame: Randomization until radiation necrosis in brain and/or spinal cord, assessed up to 3 years
measure: Incidence of treatment-related adverse events (AEs)
timeFrame: Baseline to 30 days from end of radiation therapy
measure: Patient reported outcomes (PRO)
timeFrame: Baseline to 24 months post-radiation therapy
Other outcomes:
measure: Estimates of the primary outcome treatment effect by sex
timeFrame: Up to 3 years
measure: Estimates of the primary outcome treatment effect by race
timeFrame: Up to 3 years
measure: Estimates of the primary outcome treatment effect by ethnicity
timeFrame: Up to 3 years
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Encinitas
country: United States
facility: UC San Diego Health System - Encinitas
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: San Diego
country: United States
facility: UC San Diego Medical Center - Hillcrest
state: California
city: Saint Louis
country: United States
facility: Mercy Hospital South
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
Study officials:
affiliation: NRG
name: Jonathan T Yang
role: PRINCIPAL_INVESTIGATOR
References: