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)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- NRG Oncology
- 入组人数
- 115
- 试验地点
- 60
- 主要终点
- Overall survival (OS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Lumbar Puncture (Procedure)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Lumbar Puncture (Procedure)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Involved-Field Radiation Therapy (Radiation)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Positron Emission Tomography (Procedure)
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.
干预措施: Quality-of-Life Assessment (Other)
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.
干预措施: Proton Beam Craniospinal Irradiation (Radiation)
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.
干预措施: Quality-of-Life Assessment (Other)
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.
干预措施: Positron Emission Tomography (Procedure)
结局指标
主要结局
Overall survival (OS)
时间窗: From randomization until death due to any cause, assessed up to 3 years
Will be event-driven and will be conducted when a total of 88 OS events (from both treatment arms) have been observed. The final analysis (if the trial does not stop early at an interim) is expected to occur roughly 45 months after study activation (including the initial 6-months ramp-up). All analyses (interim or final) will be done on a modified intent-to-treat (ITT) basis such that all randomized patients who have follow-up information will be included in the arm to which they are randomized regardless of what treatment the patients receive. Treatment comparisons will be based on the log-rank test. At the final analysis, if the test has an associated 1-sided p-value of 0.024 or less in favor of proton craniospinal irradiation (pCSI) (equivalently, Z \> 1.98), then the trial will conclude that the pCSI arm results in improved survival over the involved field radiotherapy (IFRT) arm.
次要结局
- Central nervous system (CNS) progression-free survival (PFS)(Randomization until CNS progression or death, whichever occurs first, assessed up to 3 years)
- Time to CNS progression(Randomization until CNS progression, assessed up to 3 years)
- Time to radiation-induced CNS necrosis (TTRN)(Randomization until radiation necrosis in brain and/or spinal cord, assessed up to 3 years)
- Incidence of treatment-related adverse events (AEs)(Baseline to 30 days from end of radiation therapy)
- Patient reported outcomes (PRO)(Baseline to 24 months post-radiation therapy)