Testing if High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus is Better at Preventing Loss of Memory and Thinking Ability
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|ClinicalTrials.gov Identifier: NCT04804644|
Recruitment Status : Recruiting
First Posted : March 18, 2021
Last Update Posted : March 28, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Metastatic Lung Small Cell Carcinoma Metastatic Malignant Neoplasm in the Brain Recurrent Lung Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8||Drug: Memantine Hydrochloride Other: Neurocognitive Assessment Radiation: Stereotactic Radiosurgery Radiation: Whole-Brain Radiotherapy||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Supportive Care|
|Official Title:||Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for 10 or Fewer Brain Metastases From Small Cell Lung Cancer|
|Actual Study Start Date :||March 24, 2021|
|Estimated Primary Completion Date :||July 1, 2025|
|Estimated Study Completion Date :||July 1, 2030|
Experimental: Arm I (SRS)
Patients undergo SRS over 1 day (in some cases several days).
Other: Neurocognitive Assessment
Radiation: Stereotactic Radiosurgery
Active Comparator: Arm II (HA-WBRT, memantine)
Patients also undergo HA-WBRT QD for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients will also receive memantine PO QD or BID for up to 24 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Memantine Hydrochloride
Other: Neurocognitive Assessment
Radiation: Whole-Brain Radiotherapy
- Time to Neurocognitive Failure [ Time Frame: 1 year ]Neurocognitive failure is the first failure, defined as neurocognitive decline (decline vs. no decline) using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, or Trail Making Test (TMT) Parts A and B.
- Preservation of Neurocognitive Function [ Time Frame: 1 year ]A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
- Perceived Difficulties in Cognition [ Time Frame: 1 year ]Measured by Patient Reported Outcomes Measurement Information System (PROMIS). For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
- Symptom Burden [ Time Frame: 1 year ]Measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT). Four subscales (symptom severity, symptom interference, neurologic factor, and cognitive factor score) as well as certain individual items (fatigue, neurologic factor items, and cognitive factor items) of the MDASI-BT will be analyzed. Mixed effects models will be used to assess changes of the four subscale scores (symptom severity, symptom interference, neurologic factor, and cognitive factor score) across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
- Overall Survival [ Time Frame: From the date of randomization to the date of death, or otherwise, the last follow-up date on which the patient was reported alive, assessed up to 10 years ]Will be estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested using the log rank test (Mantel 1966). The Cox proportional hazard model (Cox 1972) will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient specific risk factors such as number of brain metastases and its interaction with treatment, KPS, and time to salvage chemotherapy as a time varying covariate. A two-sided significance level of 0.05 will be used.
- Time to Neurologic Death [ Time Frame: From the date of randomization to the date of neurologic death, assessed up to 10 years ]Gray's test will be used to assess between treatment arm comparisons (Gray 1988). Cause-specific Cox proportional hazards models will be used to evaluate the effect of stratification variables (DS-GPA and prior NCF testing exposure) and other baseline characteristics, such as KPS, and number of brain metastases and its interaction with treatment arm. A two-sided significance level of 0.05 will be used.
- Salvage procedures used to manage recurrent intracranial disease [ Time Frame: 10 years ]Will be collected and descriptively compared between arms using Chi-square tests.
- Incidence of adverse events [ Time Frame: 10 years ]Graded by Common Terminology Criteria for Adverse Events version 5.0. Counts of all adverse events (AEs) by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The rate of grade 3+ AEs related to treatment and the rate of grade 3+ AEs regardless of relationship to treatment will be compared between treatment arms using a Chi-square test at a two-sided significance level of 0.05.
- Time to local brain recurrence (in brain lesions present at trial enrollment and treated with either stereotactic radiosurgery [SRS] or hippocampal-avoidant whole brain radiotherapy [HA-WBRT]) [ Time Frame: 10 years ]
- Time to incidence of distant brain relapses [ Time Frame: 10 years ]
- Time to leptomeningeal dissemination [ Time Frame: 10 years ]
- Time delay to salvage WBRT or HA-WBRT in patients on the SRS arm [ Time Frame: Baseline to first salvage treatment, assessed up to 10 years ]Gray's test will be used to compare treatment arms (Gray 1988).
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Pathologically (histologically or cytologically) proven diagnosis of small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);
- Patients with de novo or recurrent small cell lung cancer are permitted.
Ten or fewer brain metastases ≤ 3 cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed ≤ 21 days prior to study entry.
- Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.
- The total tumor volume must be 30 cm^3 or less. Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
Brain metastases 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 FLAIR (preferred) or T2 sequence is required. This can be acquired as a two dimensional (2D) or 3D image. If 2D, the images should be obtained in the axial plane.
- 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.
- History/physical examination
- Age ≥ 18
- Karnofsky performance status of ≥ 70
- Creatinine clearance ≥ 30 ml/min
Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.
- Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.
- Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.
- Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.
- Patients may have had prior intracranial surgical resection. Patients must have completed prior intracranial surgical resection at least 14 days prior to registration.
- Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
The patient must provide study-specific informed consent prior to study entry.
- Patients with impaired decision-making capacity are not permitted on study.
- ELIGIBILITY CRITERIA PRIOR TO STEP 2 REGISTRATION
The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.
- NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
- Planned infusion of cytotoxic chemotherapy on the same day as SRS or HA-WBRT treatment. Patients may have had prior chemotherapy. Concurrent immunotherapy is permitted.
- Prior allergic reaction to memantine.
- Intractable seizures while on adequate anticonvulsant therapy; more than 1 seizure per month for the past 2 months.
- Patients with definitive leptomeningeal metastases.
- Known history of demyelinating disease such as multiple sclerosis.
- Contraindication to MR imaging such as implanted metal devices that are MRI-incompatible, allergy to MRI contrast that cannot be adequately addressed with pre-contrast medications, or foreign bodies that preclude MRI imaging. (Questions regarding MRI compatibility of implanted objects should be reviewed with the Radiology Department performing the MRI).
- Current use of (other N-methyl-D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan.
Radiographic evidence of hydrocephalus or other architectural change of the ventricular system resulting in significant anatomic distortion of the hippocampus, including placement of external ventricular drain or ventriculoperitoneal shunt.
- Mild cases of hydrocephalus not resulting in significant anatomic distortion of the hippocampus are permitted.
- Prior radiotherapy to the brain, including SRS, WBRT, or prophylactic cranial irradiation (PCI).
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 registration
- Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04804644
|Principal Investigator:||Vinai Gondi||NRG Oncology|
|Responsible Party:||NRG Oncology|
|Other Study ID Numbers:||
NCI-2020-11651 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-CC009 ( Other Identifier: NRG Oncology )
NRG-CC009 ( Other Identifier: DCP )
NRG-CC009 ( Other Identifier: CTEP )
UG1CA189867 ( U.S. NIH Grant/Contract )
|First Posted:||March 18, 2021 Key Record Dates|
|Last Update Posted:||March 28, 2023|
|Last Verified:||March 2023|
|Studies a U.S. FDA-regulated Drug Product:||No|
|Studies a U.S. FDA-regulated Device Product:||No|
Carcinoma, Small Cell
Small Cell Lung Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents