NTS-WBRT in Brain Metastases

Phase II Trial of Normal Tissue Sparing Whole Brain Radiation Therapy (NTS-WBRT) in Patients With Brain Metastases

This research is being done to assess the quality of life and symptom burden in participants who receive (normal tissue sparing whole brain radiation therapy (NTS-WBRT).

This research study involves:

• NTS-WBRT (normal tissue sparing whole brain radiation therapy)
• Memantine standard of care drug

Study Overview

• Status: Recruiting
• Conditions: Brain Metastases
• Intervention / Treatment: Radiation: NTS-WBRT (normal tissue sparing whole brain radiation therapy); Drug: Memantine

Detailed Description

This is a Phase 2 trial testing the safety and effectiveness of NTS-WBRT (normal tissue sparing whole brain radiation therapy) in treating brain metastases.

NTS-WBRT is a targeted radiation therapy that further reduces radiation dose to tissue that does not need radiation therapy treatment.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

It is expected that about 41 people will take part in this research study.

• Study Type: Interventional
• Enrollment (Estimated): 41
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Helen A Shih, MD, MS, MPH; Phone Number: (617) 724-9627; Email: hshih@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital Cancer Center
      • Contact: Helen A Shih, MD,MS,MPH; Phone Number: 617-724-9627; Email: hshih@mgh.harvard.edu
      • Principal Investigator: Helen A Shih, MD, MS, MPH

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Any patient with a solid tumor diagnosis and any number of brain metastasis clinically indicated for cranial irradiation with whole brain radiation therapy
• Age ≥ 18
• Karnofsky Performance Status ≥ 70
• Prior stereotactic radiosurgery (SRS) permissible per physician discretion
• Prior craniotomy permissible per physician discretion. Protocol radiation therapy should be initiated ≥2 weeks after craniotomy.
• Prior partial brain radiation therapy permissible if target volume < 50% brain and per physician discretion
• Expectant > 6 months survival
• Ability to understand and the willingness to sign a written informed consent document.
• Fluency in English, able to complete questionnaires and neurocognitive testing
• Ability to undergo MRI with gadolinium examination
• Ability to return for follow-up examinations throughout the course of this study for a maximum of 2 years after radiation treatment completion
• Any prior, concomitant, or post-radiotherapy systemic therapy is permitted at discretion of treating physicians
• Negative pregnancy test for premenopausal women

Exclusion Criteria:

• Leptomeningeal disease (by any one or more of clinical assessment, radiographic assessment, or cerebrospinal fluid study)
• Prior whole brain radiation therapy
• Pre-existing or current use of memantine or other NMDA antagonists
• Known allergy to contrast used in imaging studies and/or inability to have MRI imaging
• Uncontrolled intercurrent illness that could significantly affect baseline cognitive function as determined by the enrolling clinician, such as symptomatic congestive heart failure, unstable angina pectoris, prior CVA, significant uncontrolled epilepsy or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant or unwilling to use appropriate contraception to prevent pregnancy during the time of radiation therapy
• Concurrent participation in an investigational systemic therapy protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: NTS-WBRT (normal tissue sparing whole brain radiation therapy) + Memantine; Participants will be randomly assigned to NTS-WBRT (normal tissue sparing whole brain radiation therapy) administration group and receive: NTS-WBRT for 5 days (Monday-Friday) for either 2 or 3 weeks.; Memantine per standard of care, 1-2x daily for up to 24 weeks Specific participant administration schedules will be determined by study doctor

Radiation: NTS-WBRT (normal tissue sparing whole brain radiation therapy); Radiation; Other Names: Radiation Therapy; Drug: Memantine; Capsule, taken orally; Other Names: Namenda; Namenda XR; Namenda XR Titration Pack

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Patient Reported Quality of Life for NTS-WBRT (normal tissue sparing whole brain radiation therapy)	Assessed by Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire. Score range is 0-200 and the higher the score, the better the outcome.	4 Months
Change in Patient Reported Symptom Burden for NTS-WBRT (normal tissue sparing whole brain radiation therapy)	Assessed by Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire. Score range is 0-200 and the higher the score, the better the outcome.	4 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0	The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade, compared using Fisher's exact test.	Up to 24 months
Tumor local control Rates between NTS-WBRT+SIB and NTS-WBRT	Estimated by the cumulative incidence function treating death as a competing risk, compared using Gray's test	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Intracranial- Progression Free Survival (PFS) between NTS-WBRT+SIB and NTS-WBRT	Estimated using the Kaplan-Meier method, compared using the logrank test	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Overall survival (OS) between NTS-WBRT+SIB and NTS-WBRT	Estimated using the Kaplan-Meier method, compared using the logrank test	The date of randomization to the date of death, or otherwise censored at the last follow-up date for patients still alive up to 24 months
Change in Neurocognitive function between NTS-WBRT+SIB and NTS-WBRT	Assessed longitudinally by the HADS-D and HADS-A questionnaires	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Mood between NTS-WBRT+SIB and NTS-WBRT	Mixed effects models with treatment arm as a fixed effect will be used to compare changes in depression (HADS-D) and anxiety (HADS-A) scores over time	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Fatigue between NTS-WBRT+SIB and NTS-WBRT	Mixed effects models with treatment arm as a fixed effect will be used to compare changes in the fatigue score over time	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Neuroendocrine function between NTS-WBRT+SIB and NTS-WBRT	Estimated by the cumulative incidence function treating intracranial progression and death as competing risks; compared using Gray's test.	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Hearing between NTS-WBRT+SIB and NTS-WBRT Assessed by Pure Tone Average	Changes in pure tone average (PTA) from baseline to each subsequent assessment will be compared between treatment arms using Wilcox rank-sum test. Pure tone thresholds are found by presenting tones using standard headphones and methods in a sound treated booth. Pure tone thresholds will be tested by both bone (500, 1000, 2000 and 4000 Hz) and air conduction (250, 500, 1000, 2000, 3000, 4000, 6000, 8000, 10000, 12000, and 14000 Hz). Masking will be applied sufficient to determine the ear responsible for each value. The results of this testing will be used to determine the sensorineural hearing level. If significant conductive loss is found, bone conduction threshold will be used to report sensory ototoxicity. Threshold effects across frequency will be combined into a Pure Tone Average (PTA), defined as the average of audiometric thresholds at 500, 1000, 2000, and 4000. A significant decrease in Pure Tone Average is defined as an increase > 10 dB in relation to baseline threshold.	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Hearing between NTS-WBRT+SIB and NTS-WBRT Assessed by Word Recognition Score	Changes in word recognition score (WRS) from baseline to each subsequent assessment will be compared between treatment arms using Wilcox rank-sum test. Word recognition is defined as the percent correct on a standard, 50-item word list of English monosyllables: CID W-22, NU#6 or CNC. A significant decrease in word recognition is defined as a score exceeding the 95% critical difference from the table of Thornton and Raffin.	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Change in Hearing between NTS-WBRT+SIB and NTS-WBRT Assessed by Otoacoustic Emissions	The rates of absent otoacoustic emissions (OAE) will be compared between treatment arms using Fisher's exact test. The OAE (Otoacoustic Emissions) test checks part of the inner ear's response to sound. Otoacoustic emissions are sounds given off by one small part of the cochlea when it is stimulated by soft clicking sounds. When the sound stimulates the cochlea, the outer hair cells vibrate. The vibration produces a nearly inaudible sound that echoes back into the middle ear. The results are either present or absent. Present OAEs are consistent with normal to near normal hearing. Absent OAEs may be a sign of a problem related to study treatment.	baseline, 2, 4, 6, 9, 12, 18 and 24 months
Alopecia Rates between NTS-WBRT+SIB and NTS-WBRT	Assessed by patient report and visual inspection with documented photography; compared by Fisher's exact test	baseline, 2, 4, 6, 9, 12, 18 and 24 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Helen A Shih, MD, MS, MPH, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: August 6, 2021
• First Submitted That Met QC Criteria: August 18, 2021
• First Posted (Actual): August 19, 2021

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Brain Metastases
• 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; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: 21-356

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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