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Pilot Phase 2 Study Whole Brain Radiation Therapy With Simultaneous Integrated Boost for Patients With Brain Metastases

NCT03189381

Description:

This trial is a pilot, Phase 2, sequential two-cohort study designed to test two de-escalated whole brain radiation therapy (WBRT) dose levels and assess their ability to maintain acceptable in-brain distant control. The WBRT dose would decrease as the study moves forward, both in terms of absolute value and equivalent dose in 2 Gray fractions (EQD2) (as determined by the linear quadratic radiobiological model). The absolute value of the simultaneous integrated boost (SIB) dose will change with each dose level because the number of fractions delivered will depend on the WBRT dose. As such, the SIB dose will be manipulated such that the EQD2 will remain essentially equivalent despite the difference in the number of fractions delivered. This design will ensure that the only variable is the change in WBRT dose. The concept is that WBRT with SIB would be expected to maximize both local and in-brain distant control as has already been shown in studies exploring WBRT with SRS boost. However, by itself WBRT with SIB does not address the concern over neurocognitive outcomes. Therefore, investigators hypothesize that there is a lower WBRT dose threshold that will maintain acceptable in-brain distant control, particularly in the setting of a SIB to gross lesions to maintain treated lesion control. In addition, lower overall brain dose (including lower hippocampal dose without specific hippocampal avoidance) may potentially improve neurocognitive function. Investigators are also interested in evaluating treated lesion control, overall survival, neurocognitive sequelae of therapy, quality of life, performance status, and adverse effects of therapy. Biomarker identification for potential correlative circulating tumor DNA and microRNA is an exploratory endpoint to generate data for future prospective evaluation.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pilot Phase 2 Study Whole Brain Radiation Therapy With Simultaneous Integrated Boost for Patients With Brain Metastases
  • Official Title: A Pilot Phase 2 Study Evaluating Dose De-escalation in Whole Brain Radiation Therapy With Simultaneous Integrated Boost for Patients With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: IUSCC-0605
  • NCT ID: NCT03189381

Conditions

  • Brain Metastases

Purpose

This trial is a pilot, Phase 2, sequential two-cohort study designed to test two de-escalated whole brain radiation therapy (WBRT) dose levels and assess their ability to maintain acceptable in-brain distant control. The WBRT dose would decrease as the study moves forward, both in terms of absolute value and equivalent dose in 2 Gray fractions (EQD2) (as determined by the linear quadratic radiobiological model). The absolute value of the simultaneous integrated boost (SIB) dose will change with each dose level because the number of fractions delivered will depend on the WBRT dose. As such, the SIB dose will be manipulated such that the EQD2 will remain essentially equivalent despite the difference in the number of fractions delivered. This design will ensure that the only variable is the change in WBRT dose. The concept is that WBRT with SIB would be expected to maximize both local and in-brain distant control as has already been shown in studies exploring WBRT with SRS boost. However, by itself WBRT with SIB does not address the concern over neurocognitive outcomes. Therefore, investigators hypothesize that there is a lower WBRT dose threshold that will maintain acceptable in-brain distant control, particularly in the setting of a SIB to gross lesions to maintain treated lesion control. In addition, lower overall brain dose (including lower hippocampal dose without specific hippocampal avoidance) may potentially improve neurocognitive function. Investigators are also interested in evaluating treated lesion control, overall survival, neurocognitive sequelae of therapy, quality of life, performance status, and adverse effects of therapy. Biomarker identification for potential correlative circulating tumor DNA and microRNA is an exploratory endpoint to generate data for future prospective evaluation.

Detailed Description

      Primary Objective Evaluate two de-escalated whole brain radiation dose levels (in the setting
      of simultaneous integrated boost to gross lesions) with respect to in-brain distant control
      for brain metastases, defined as an in-brain failure rate outside of the planning target
      volume at 6 months of < 20%.

      Secondary Objectives

        1. Evaluate treated lesion control at 6 months for brain metastases in the setting of a
           predetermined total biologically effective SIB dose as determined by radiographic
           progression within the planning target volume with fusion and overlay of follow-up MRIs.

        2. Evaluate overall survival at 6 months for brain metastases in the setting of WBRT with
           SIB.

        3. Evaluate changes in neurocognitive function after WBRT with SIB in the following
           domains: verbal learning and memory as assessed by the Hopkins Verbal Learning Test -
           Revised (HVLT-R); memory, executive function, and higher order cognition as assessed by
           the Groton Maze Learning Test; and working memory via either the Two Back Test or One
           Back Test (depending on patient performance at baseline). All tests except the HVLT-R
           are part of a custom battery designed with the help of CogState psychology staff and
           will be delivered via the CogState platform.

        4. Evaluate changes in health-related quality of life as assessed by the Functional
           Assessment of Cancer Therapy with Brain Subscale (FACT-Br) after WBRT-SIB for brain
           metastases.

        5. Evaluate changes in performance status as assessed by the Karnofsky Performance Status
           tool after WBRT-SIB for brain metastases.

        6. Evaluate adverse events after WBRT-SIB for brain metastases according to current CTCAE
           criteria and documented by the LENT-SOMA form.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalStandard PCI dose
    Cohort BExperimentalLow PCI dose

      Eligibility Criteria

              Inclusion Criteria
      
                1. Age ≥ 18 at time of consent.
      
                2. Ability to provide written informed consent and HIPAA authorization.
      
                3. Pathological diagnosis of any solid tumor histology (from any site in the body).
      
                4. Pathological or clinical (i.e., by imaging) diagnosis of brain metastatic tumor
                   lesions.
      
                5. Total volume of lesions ≤ 30 cm3.
      
                6. Maximum volume of largest lesion ≤ 5 cm3.
      
                   a. This volume limit would be equivalent to a largest diameter of about 2.1 cm,
                   assuming a perfect sphere.
      
                7. Not a candidate for or eligible for but refused Gamma Knife radiosurgery.
      
              Exclusion Criteria
      
                1. Previous radiation to the brain, including WBRT or brain radiosurgery.
      
                2. Life expectancy < 6 months (as estimated per ds-GPA).
      
                3. Inability to comply with treatment per investigator discretion.
      
                4. Inability to complete neurocognitive assessments per investigator discretion.
      
              Of note, tumor lesion number is not an inclusion or exclusion criteria as we are using
              volume-based criteria instead.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:In-brain distant failure rate
      Time Frame:6 months
      Safety Issue:
      Description:An actuarial 6-month rate of new parenchymal lesions seen outside the planning target volume of any lesion that received SIB on any post-treatment MRI (in all 3 planes)

      Secondary Outcome Measures

      Measure:Treated lesion control
      Time Frame:6 months
      Safety Issue:
      Description:An actuarial 6-month rate of any new, recurrent, or progressing (as defined by Response Assessment in Neuro-Oncology Brain Metastases criteria) tumor within the planning target volume on any post-treatment MRI
      Measure:Overall survival
      Time Frame:6 months
      Safety Issue:
      Description:An actuarial 6-month rate of patients still alive regardless of disease status
      Measure:Change in neurocognitive function
      Time Frame:6 months
      Safety Issue:
      Description:Total change in score of neurocognitive tests (Hopkins Verbal Learning Test - Revised, Groton Maze, and Two or One Back Test)
      Measure:Change in health-related quality of life
      Time Frame:6 months
      Safety Issue:
      Description:Total change in score of health-related quality of life test (Functional Assessment of Cancer Therapy with Brain Subscale)
      Measure:Change in performance status
      Time Frame:6 months
      Safety Issue:
      Description:Total change in performance status score (Karnofsky)
      Measure:Incidence of early and late adverse effects
      Time Frame:1 year
      Safety Issue:
      Description:Adverse effects will be defined per CTCAE

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Indiana University

      Trial Keywords

      • Whole Brain Radiation
      • Simultaneous Integrated Boost

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