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

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

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.

Study Overview

• Status: Terminated
• Conditions: Brain Metastases
• Intervention / Treatment: Radiation: Cohort A; Radiation: Cohort B

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).
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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hospital
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 current ds-GPA).
3. 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.
4. Inability to comply with treatment per investigator discretion.
5. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

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). This is the binomial proportion of patients who experienced in-brain distant failure by 6 months and the associated 95% confidence interval.	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treated Lesion Local Control	An actuarial 6-month rate of any new, recurrent, or progressing (as defined by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria) tumor within the planning target volume on any post-treatment MRI. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last know alive or at the date of death if they expired.	6 Months
Overall Survival for Evaluable Patients	An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive.	6 Months
Change in Neurocognitive Function From Baseline to 6 Months	The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better).	6 Months
Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months	The change in scores of health-related quality of life test from baseline to 6 months calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase in score from baseline to 6 months while negative values indicate a decrease. The Functional Assessment of Cancer Therapy with Brain Subscale (FACT-Br) asks questions on a scale from 0 to 4 with 0 being "not at all" and 4 being "very much". Responses were reversed, if applicable, and compiled to calculate physical well-being (range: 0-28), social/family well-being (range: 0-28), emotional well-being (range: 0-24), functional well-being (range: 0-28), bone marrow transplant (BMT) (range: 0-40), and brain cancer (range: 0-92) subscale scores. These subscale scores were then summed to obtain the trail outcome index (range: 0-148), bone marrow transplant (FACT-BMT) (range: 0-96), general (FACT-G) (range: 0-108), and FACT-Br (range: 0-200) total scores. The higher the score, the better the QoL.	6 Months
Change in Performance Status	Total change in performance status score was calculated by substracting the baseline score from the follow-up score. Positive values indicate an increase in score from baseline while negative values indicate a decrease in score from baseline. Functional status evaluated using the Karnofsky Performance Score (KPS) Index. The KPS score is evaluated on a scale from 0 to 100 where 0 is death and 100 is "normal no complaints; no evidence of disease".	12 Months
Incidence of Early and Late Treatment-Related Adverse Effects	This is the percentage of eligible patients who experienced the respective treatment-related AE while on study. Adverse effects (AEs) were defined per CTCAE and considered treatment-related if the AE start date occurred on or after the first date of treatment and it was possibly, probably, or definitely related to treatment. AEs were recorded from the start of treatment until the patient was off-study.	Up To 39 Months
Overall Survival for Eligible Patients	An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive.	6 Months
Change in Neurocognitive Function Retention Percentage Raw Score From Baseline to 6 Months	The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better).	6 Months

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Kevin R. Shiue, MD, Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2017
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: June 14, 2017
• First Submitted That Met QC Criteria: June 14, 2017
• First Posted (Actual): June 16, 2017

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 26, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Simultaneous Integrated Boost; Whole Brain Radiation
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: IUSCC-0605

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes