Clinical trial NCT04588246: Comparing Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in Patients With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery
Official title: Phase III Trial of Stereotactic Radiosurgery (SRS) or Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Distant Brain Relapse With Brain Metastasis Velocity &gt;/= 4 Brain Metastases/Year
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Anatomic Stage IV Breast Cancer AJCC v8
Metastatic Lung Non-Small Cell Carcinoma
Metastatic Lung Small Cell Carcinoma
Metastatic Malignant Breast Neoplasm
Metastatic Malignant Digestive System Neoplasm
Metastatic Malignant Neoplasm in the Brain
Metastatic Malignant Solid Neoplasm
Metastatic Melanoma
Metastatic Renal Cell Carcinoma
Recurrent Brain Neoplasm
Stage IV Lung Cancer AJCC v8
Stage IV Renal Cell Cancer AJCC v8
Lead sponsor: NRG Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2020-10-19
Enrollment: 19
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 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.

Detailed description: 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.

III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS.

IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

V. To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

VI. To tabulate and descriptively compare the adverse events associated with the interventions.

VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.

EXPLORATORY OBJECTIVES:

I. To collect serum, plasma, and whole blood for translational research analyses.

II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.

III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.

IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.

V. To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS.

VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity \>= 4 new brain metastases/year.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: 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 orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial.

ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.

Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Percentage of Participants With Neurologic Death
timeFrame: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Secondary outcomes:
measure: Overall Survival
timeFrame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
measure: Intracranial Progression-Free Survival (IPFS)
timeFrame: Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
measure: Brain Metastasis Velocity at Subsequent Relapse (BMVs)
timeFrame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
measure: Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score
timeFrame: Baseline and 4 months from treatment start
measure: Number of Participants With a Grade 3 or Higher Adverse Event
timeFrame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
measure: Number of Participants Who Received Salvage Procedures
timeFrame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center - Tucson
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Corona
country: United States
facility: City of Hope Corona
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Irvine
country: United States
facility: City of Hope at Irvine Lennar
state: California
city: Lancaster
country: United States
facility: City of Hope Antelope Valley
state: California
city: Roseville
country: United States
facility: Sutter Cancer Centers Radiation Oncology Services-Roseville
state: California
city: Roseville
country: United States
facility: Sutter Roseville Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter Medical Center Sacramento
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center-Pacific Campus
state: California
city: South Pasadena
country: United States
facility: City of Hope South Pasadena
state: California
city: Torrance
country: United States
facility: City of Hope South Bay
state: California
city: Upland
country: United States
facility: City of Hope Upland
state: California
city: Newark
country: United States
facility: Delaware Clinical and Laboratory Physicians PA
state: Delaware
city: Newark
country: United States
facility: Helen F Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants PA
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Hospital West
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Danville
country: United States
facility: Carle at The Riverfront
state: Illinois
city: DeKalb
country: United States
facility: Northwestern Medicine Cancer Center Kishwaukee
state: Illinois
city: Effingham
country: United States
facility: Carle Physician Group-Effingham
state: Illinois
city: Geneva
country: United States
facility: Northwestern Medicine Cancer Center Delnor
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Urbana
country: United States
facility: The Carle Foundation Hospital
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: MedStar Franklin Square Medical Center/Weinberg Cancer Institute
state: Maryland
city: Bel Air
country: United States
facility: UM Upper Chesapeake Medical Center
state: Maryland
city: Columbia
country: United States
facility: Central Maryland Radiation Oncology in Howard County
state: Maryland
city: Glen Burnie
country: United States
facility: UM Baltimore Washington Medical Center/Tate Cancer Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Brighton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Brighton
state: Michigan
city: Chelsea
country: United States
facility: Chelsea Hospital
state: Michigan
city: Chelsea
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Lake Success
country: United States
facility: Northwell Health/Center for Advanced Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Verona
country: United States
facility: Upstate Cancer Center at Verona
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Chadds Ford
country: United States
facility: Christiana Care Health System-Concord Health Center
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Greensburg
country: United States
facility: UPMC Cancer Centers - Arnold Palmer Pavilion
state: Pennsylvania
city: Lewisburg
country: United States
facility: Geisinger Medical Oncology-Lewisburg
state: Pennsylvania
city: Media
country: United States
facility: Riddle Memorial Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC-Shadyside Hospital
state: Pennsylvania
city: Pottsville
country: United States
facility: Geisinger Cancer Services-Pottsville
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: York
country: United States
facility: UPMC Memorial
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Faris
state: South Carolina
city: Lubbock
country: United States
facility: Covenant Medical Center-Lakeside
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
city: Menomonee Falls
country: United States
facility: Froedtert Menomonee Falls Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Oak Creek
country: United States
facility: Drexel Town Square Health Center
state: Wisconsin
city: West Bend
country: United States
facility: Froedtert West Bend Hospital/Kraemer Cancer Center
state: Wisconsin
city: Montreal
country: Canada
facility: CHUM - Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Chai Wan
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
Study officials:
affiliation: NRG Oncology
name: Vinai Gondi
role: PRINCIPAL_INVESTIGATOR
References: