Phase III Trial of Stereotactic Radiosurgery (SRS) or Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Distant Brain Relapse With Brain Metastasis Velocity >/= 4 Brain Metastases/Year
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- NRG Oncology
- 入组人数
- 19
- 试验地点
- 161
- 主要终点
- Percentage of Participants With Neurologic Death
研究概览
简要总结
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.
详细描述
PRIMARY OBJECTIVE:
I. To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS).
SECONDARY OBJECTIVES:
I. To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs overall survival as compared to SRS.
II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity >= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS.
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
- Single (Investigator)
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
- •Patients must have developed their distant brain relapse(s) at least 8 weeks after last SRS and within 21 days prior to randomization
- •Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic MRI brain scan obtained within 21 days prior to randomization
- •"last SRS" refers to the most recent SRS procedure that the patient received prior to enrollment on this study
- •Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
- •REQUIRED MRI ELEMENTS
- •Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm
- •Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged)
- •A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
- •ADDITIONAL RECOMMENDATIONS
- •Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence
- •Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1
- •Recommendation is that imaging be performed on a 3 Tesla (3T) MRI
- •Recommendation is that the study participants be scanned on the same MRI instrument at each time point
- •Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020
- •If additional sequences are obtained, total imaging time should not exceed 60 minutes
- •Brain metastasis velocity (BMV) since last SRS must be >= 4 brain metastases/year
- •The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
- •Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
- •Other histologies are not permitted
- •History and physical examination within 28 days prior to randomization
- •Age >= 18
- •Karnofsky performance status of >= 70 within 28 days prior to randomization
- •Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
- •Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
- •Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
排除标准
- •BMV >= 4 brain metastases/year at time of any SRS prior to enrollment.
- •Patients are permitted to have undergone multiple SRS treatments to different brain metastases so long as prior BMV has been less than 4 brain metastases/year
- •Prior WBRT or prophylactic cranial irradiation
- •Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
- •Brain metastases from primary germ cell tumor or lymphoma
- •Definitive leptomeningeal metastasis
- •Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
- •Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
- •Known history of demyelinating disease such as multiple sclerosis
- •Inability to swallow pills
- •Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
- •Contraindications to memantine, including:
- •Allergy, including prior allergic reaction to memantine
- •Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
- •Current use of N-methyl-D-asparatate (NMDA) agonist
- •Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
- •Severe, active co-morbidity defined as follows:
- •Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- •Transmural myocardial infarction within the last 6 months
- •Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
- •Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
- •Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
- •Renal tubular acidosis or metabolic acidosis
- •Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol
- •Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus
研究组 & 干预措施
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Quality-of-Life Assessment (Other)
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Questionnaire Administration (Other)
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Memantine (Drug)
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Stereotactic Radiosurgery (Radiation)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Whole-Brain Radiotherapy (Radiation)
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Arm II (SRS/fSRS)
Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Quality-of-Life Assessment (Other)
Arm I (memantine, HA-WBRT)
Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Percentage of Participants With Neurologic Death
时间窗: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done.
次要结局
- Overall Survival(Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.)
- Intracranial Progression-Free Survival (IPFS)(Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.)
- Brain Metastasis Velocity at Subsequent Relapse (BMVs)(Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.)
- Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score(Baseline and 4 months from treatment start)
- Number of Participants With a Grade 3 or Higher Adverse Event(Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.)
- Number of Participants Who Received Salvage Procedures(Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.)