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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

Trial Status: Active

This phase III trial compares the effect of stereotactic radiosurgery to standard of care memantine and whole brain radiation therapy that avoids the hippocampus (the memory zone of the brain) for the treatment of small cell lung cancer that has spread to the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Whole brain radiation therapy delivers a low dose of radiation to the entire brain including the normal brain tissue. Hippocampal avoidance during whole-brain radiation therapy (HA-WBRT) decreases the amount of radiation that is delivered to the hippocampus which is a brain structure that is important for memory. The drug, memantine, is also often given with whole brain radiotherapy because it may decrease the risk of side effects related to thinking and memory. Stereotactic radiosurgery may decrease side effects related to memory and thinking compared to standard of care HA-WBRT plus memantine.

Inclusion Criteria

  • 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. ** 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.
  • History/physical examination within 28 days prior to registration
  • Age >= 18
  • Karnofsky performance status of >= 70 within 28 days prior to registration
  • Creatinine clearance >= 30 ml/min (within 28 days prior to registration)
  • 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 1 business day 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.

Exclusion Criteria

  • 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

Arizona

Phoenix
Mayo Clinic Hospital in Arizona
Status: ACTIVE
Contact: Site Public Contact
Phone: 855-776-0015

California

Los Angeles
Los Angeles County-USC Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-865-0451
USC / Norris Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-865-0451

Colorado

Aurora
University of Colorado Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 720-848-0650
Colorado Springs
Memorial Hospital North
Status: ACTIVE
Contact: Site Public Contact
Phone: 719-364-6700
UCHealth Memorial Hospital Central
Status: ACTIVE
Contact: Site Public Contact
Phone: 719-365-2406

Delaware

Newark
Christiana Care Health System-Christiana Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-623-4450
Delaware Clinical and Laboratory Physicians PA
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-623-4450
Helen F Graham Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-623-4450
Medical Oncology Hematology Consultants PA
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-623-4450

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Site Public Contact
Phone: 352-273-8010

Georgia

Atlanta
Emory Saint Joseph's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-851-7115
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-778-1868
Emory University Hospital Midtown
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-946-7447
Northside Hospital
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Contact: Site Public Contact
Phone: 404-303-3355
Canton
Northside Hospital-Cherokee
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Contact: Site Public Contact
Phone: 404-303-3355
Cumming
Northside Hospital-Forsyth
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-303-3355

Illinois

Centralia
Centralia Oncology Clinic
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4762
Chicago
Rush University Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 312-942-5498
University of Chicago Comprehensive Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 773-702-8222
Danville
Carle on Vermilion
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
DeKalb
Northwestern Medicine Cancer Center Kishwaukee
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-352-5360
Decatur
Cancer Care Specialists of Illinois - Decatur
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4762
Decatur Memorial Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4762
Effingham
Carle Physician Group-Effingham
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Crossroads Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4762
Geneva
Northwestern Medicine Cancer Center Delnor
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-352-5360
Mattoon
Carle Physician Group-Mattoon / Charleston
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
O'Fallon
Cancer Care Center of O'Fallon
Status: ACTIVE
Contact: Site Public Contact
Phone: 217-876-4762
Urbana
Carle Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
The Carle Foundation Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-446-5532
Warrenville
Northwestern Medicine Cancer Center Warrenville
Status: ACTIVE
Contact: Site Public Contact
Phone: 630-352-5360

Iowa

Ames
Mary Greeley Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-956-4132
McFarland Clinic PC - Ames
Status: ACTIVE
Contact: Site Public Contact
Phone: 515-239-4734

Louisiana

Baton Rouge
Mary Bird Perkins Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 225-215-1353

Maryland

Annapolis
Anne Arundel Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 443-481-1320
Baltimore
MedStar Franklin Square Medical Center / Weinberg Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 443-777-7364
University of Maryland / Greenebaum Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-888-8823
Bel Air
UM Upper Chesapeake Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 443-643-3010
Columbia
Central Maryland Radiation Oncology in Howard County
Status: ACTIVE
Contact: Site Public Contact
Phone: 443-546-1300
Easton
University of Maryland Shore Medical Center at Easton
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-822-1000
Salisbury
TidalHealth Peninsula Regional
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-543-7032

Massachusetts

Boston
Boston Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 617-638-8265

Michigan

Ann Arbor
Saint Joseph Mercy Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Brighton
Saint Joseph Mercy Brighton
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Canton
Saint Joseph Mercy Canton
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Trinity Health IHA Medical Group Hematology Oncology - Canton
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Chelsea
Saint Joseph Mercy Chelsea
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Livonia
Trinity Health Saint Mary Mercy Livonia Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251
Ypsilanti
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 734-712-7251

Minnesota

Bemidji
Sanford Joe Lueken Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 218-333-5000
Coon Rapids
Mercy Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 952-993-1517
Fridley
Unity Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 952-993-1517
Maple Grove
Fairview Clinics and Surgery Center Maple Grove
Status: ACTIVE
Contact: Site Public Contact
Phone: 952-993-1517

Missouri

Cape Girardeau
Saint Francis Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 573-334-2230
Email: sfmc@sfmc.net
Farmington
Parkland Health Center - Farmington
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-996-5569
Saint Louis
Missouri Baptist Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-996-5569
Sainte Genevieve
Sainte Genevieve County Memorial Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-996-5569
Springfield
Mercy Hospital Springfield
Status: ACTIVE
Contact: Site Public Contact
Phone: 417-269-4520
Sullivan
Missouri Baptist Sullivan Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-996-5569
Sunset Hills
Missouri Baptist Outpatient Center-Sunset Hills
Status: ACTIVE
Contact: Site Public Contact
Phone: 314-996-5569

Montana

Great Falls
Benefis Healthcare- Sletten Cancer Institute
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 406-969-6060

New York

Bronx
Montefiore Medical Center - Moses Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 718-379-6866
Montefiore Medical Center-Einstein Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 718-379-6866
Montefiore Medical Center-Weiler Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 718-379-6866
Syracuse
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Site Public Contact
Phone: 315-464-5476

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-713-6771

North Dakota

Bismarck
Sanford Bismarck Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 701-323-5760
Fargo
Sanford Broadway Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 701-323-5760
Sanford Roger Maris Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 701-234-6161

Ohio

Cincinnati
University of Cincinnati Cancer Center-UC Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 513-584-7698
Cleveland
Case Western Reserve University
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-641-2422
Mentor
UH Seidman Cancer Center at Lake Health Mentor Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-641-2422
West Chester
University of Cincinnati Cancer Center-West Chester
Status: ACTIVE
Contact: Site Public Contact
Phone: 513-584-7698

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 405-271-8777

Pennsylvania

Chadds Ford
Christiana Care Health System-Concord Health Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 302-623-4450
Danville
Geisinger Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 570-271-5251
Erie
Saint Vincent Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 814-452-5000
Lewisburg
Geisinger Medical Oncology-Lewisburg
Status: ACTIVE
Contact: Site Public Contact
Phone: 570-374-8555
Philadelphia
Jefferson Torresdale Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 215-600-9151
Thomas Jefferson University Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 215-600-9151
Pittsburgh
Allegheny General Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-284-2000
Wilkes-Barre
Geisinger Wyoming Valley / Henry Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 570-271-5251

South Carolina

Florence
McLeod Regional Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 843-777-0770
Gaffney
Gibbs Cancer Center-Gaffney
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-560-6104
Greenwood
Self Regional Healthcare
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-725-4771
Greer
Gibbs Cancer Center-Pelham
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-560-6104
Spartanburg
Spartanburg Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-560-6104
Union
MGC Hematology Oncology-Union
Status: ACTIVE
Contact: Site Public Contact
Phone: 864-560-6104

South Dakota

Sioux Falls
Avera Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 605-322-3095
Sanford Cancer Center Oncology Clinic
Status: ACTIVE
Contact: Site Public Contact
Phone: 605-312-3320
Sanford USD Medical Center - Sioux Falls
Status: ACTIVE
Contact: Site Public Contact
Phone: 605-312-3320

Wisconsin

Antigo
Langlade Hospital and Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 715-623-9869
La Crosse
Gundersen Lutheran Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 608-775-2385
Madison
University of Wisconsin Carbone Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-622-8922
Wausau
Aspirus Regional Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-405-6866

PRIMARY OBJECTIVE:

I. Determine whether stereotactic radiosurgery (SRS) relative to whole brain radiotherapy with hippocampal avoidance (HA-WBRT) plus memantine hydrochloride (memantine) for brain metastases from small cell lung cancer (SCLC) prevents cognitive function failure as measured by cognitive decline on a battery of tests: the Hopkins Verbal Learning Test – Revised (HVLT-R), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT).

SECONDARY OBJECTIVES:

I. Determine whether SRS relative to HA-WBRT plus memantine for brain metastases from SCLC preserves cognitive function as separately measured by the HVLT-R, COWA, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP).

II. Assess perceived difficulties in cognitive abilities using Patient Reported Outcomes Measurement Information System (PROMIS) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

III. Assess symptom burden using the MD Anderson Symptom Inventory for brain tumor (MDASI-BT) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

IV. Compare cumulative incidence of intracranial disease progression after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

V. Compare overall survival after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

VI. Compare cumulative incidence of neurologic death after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

VII. Compare the number of salvage procedures used to manage recurrent intracranial disease following SRS relative to HA-WBRT plus memantine for SCLC brain metastases.

VIII. Compare adverse events between the treatment arms according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria.

IX. Compare the risk of developing cerebral necrosis between SRS and HA-WBRT plus memantine in patients receiving concurrent immunotherapy.

EXPLORATORY OBJECTIVES:

I. Compare cumulative incidence of local brain recurrence, distant brain relapse, and leptomeningeal dissemination after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

II. Compare the cost of brain-related therapies and quality-adjusted life years in patients who receive SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

III. Evaluate the time delay to salvage WBRT or HA-WBRT in patients enrolled on the SRS arm.

IV. Evaluate whether a time delay for chemotherapy in patients receiving HA-WBRT plus memantine relative to SRS for brain metastases from SCLC has an effect on overall survival.

V. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.

VI. Evaluate the correlation between neurocognitive functioning and patient-reported outcomes.

VII. Collect serum, plasma and imaging studies for future translational research analyses.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo SRS over 1 day (in some cases several days).

ARM II: Patients undergo HA-WBRT once daily (QD) for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive memantine orally (PO) QD or twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months for 1 year, and then every 6 months thereafter.

Trial Phase Phase III

Trial Type Supportive care

Lead Organization
NRG Oncology

Principal Investigator
Vinai Gondi

  • Primary ID NRG-CC009
  • Secondary IDs NCI-2020-11651
  • Clinicaltrials.gov ID NCT04804644