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

Study Overview
=================
Brief Summary
-----------------
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 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. Evaluate overall survival at 6 months for brain metastases in the setting of WBRT with SIB. 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). 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. Evaluate changes in performance status as assessed by the Karnofsky Performance Status tool after WBRT-SIB for brain metastases. Evaluate adverse events after WBRT-SIB for brain metastases according to current CTCAE criteria.

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

Conditions
-----------------
Brain Metastases

Intervention / Treatment
-----------------
* Radiation: Cohort A
* Radiation: Cohort B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Age ≥ 18 at time of consent. Ability to provide written informed consent and HIPAA authorization. Pathological diagnosis of any solid tumor histology (from any site in the body). Pathological or clinical (i.e., by imaging) diagnosis of brain metastatic tumor lesions. Total volume of lesions ≤ 30 cm3. 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. Not a candidate for or eligible for but refused Gamma Knife radiosurgery. Exclusion Criteria Previous radiation to the brain, including WBRT or brain radiosurgery. Life expectancy < 6 months (as estimated per current ds-GPA). For histologies not included in the ds-GPA publications or otherwise noted online at brainmetgpa.com, the PI will use either published or validated data, or the PI's best clinical judgment to determine the patient's expected survival. Inability to comply with treatment per investigator discretion. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Standard PCI dose | Radiation: Cohort A<br>* Cohort A - WBRT dose = 25 Gy, SIB dose = 42 Gy, # of daily fractions = 10, SIB dose in EQD2 = 49.7 Gy<br>|
| Experimental: Cohort B<br>Low PCI dose | Radiation: Cohort B<br>* Cohort B - WBRT dose = 20 Gy, SIB dose = 40 Gy, # of daily fractions = 8, SIB dose in EQD2 = 50.0 Gy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-brain distant failure rate | 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) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treated lesion control | 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 | 6 months | 
| Overall survival | An actuarial 6-month rate of patients still alive regardless of disease status | 6 months | 
| Change in neurocognitive function | Total change in score of neurocognitive tests (Hopkins Verbal Learning Test - Revised, Groton Maze, and Two or One Back Test) | 6 months | 
| Change in health-related quality of life | Total change in score of health-related quality of life test (Functional Assessment of Cancer Therapy with Brain Subscale) | 6 months | 
| Change in performance status | Total change in performance status score (Karnofsky) | 6 months | 
| Incidence of early and late adverse effects | Adverse effects will be defined per CTCAE | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Whole Brain Radiation, Simultaneous Integrated Boost