Optimizing Neurocognition With Whole Brain Radiation Therapy (WBRT) Using Upfront Pulsed Reduced Dose-Rate (PRDR) Technique

Optimizing Neurocognition With Whole Brain Radiation Therapy (WBRT) Using Upfront Pulsed Reduced Dose-Rate (PRDR) Technique (ONCO-RT) - A Phase II Trial of Upfront Pulsed Reduced Dose Rate Whole-Brain Radiation Therapy for Brain Metastases

Study patients will receive Whole-brain radiation therapy (WBRT) - pulsed reduced dose rate (PRDR) within 14 days of registration. All patients will receive single daily fractions using 3D conformal radiotherapy. A dose of 30 Gy in 10 fractions will be delivered using the PRDR technique.

Study Overview

• Status: Recruiting
• Conditions: Brain Metastases
• Intervention / Treatment: Drug: Memantine -Twice Daily or Extended Release; Radiation: WBRT utilizing the PRDR technique

Detailed Description

This is a phase II, single-arm, multi-center study assessing the feasibility and tolerance of WBRT using upfront PRDR in the treatment of solid tumor brain metastases. This study will also examine the impact of substituting PRDR for standard whole-brain radiation therapy in the upfront treatment of brain metastases on neurocognitive decline as compared to historical controls. Additionally, clinical patient outcomes associated with radiation treatment of brain metastases will be collected. Using a group sequential design with one interim analysis to stop for futility, the investigators will recruit and enroll 53 adult patients (≥18 years) undergoing upfront treatment of brain metastases to determine feasibility and a preliminary analysis after the first 27 enrolled patients.

In order to be eligible for this study, patients must have a biopsy-proven solid malignancy with intracranial lesions radiographically consistent with or pathologically proven to be brain metastases. Patient who are confirmed to meet all eligibility criteria will be registered to the study and start PRDR WBRT within two weeks postregistration. Patients will receive PRDR WBRT as a dose of 30Gy in 10 fractions and start memantine orally two days prior to (or one day prior to) but no later than the fourth PRDR WBRT treatment session.

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Medical College of Wisconsin Cancer Center Clinical Trials Office; Phone Number: 8900 866-680-0505; Email: cccto@mcw.edu

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert Hospital & the Medical College of Wisconsin
      • Contact: Michael Straza, MD; Phone Number: 414-805-4400; Email: mstraza@mcw.edu
    • Milwaukee, Wisconsin, United States, 53295
      • Recruiting
      • Clement J. Zablocki Veterans Affairs Medical Center
      • Contact: Amber Bishop, MS, MA; Phone Number: 42593 414-384-2000; Email: amber.bishop@va.gov
      • Principal Investigator: Lindsay Puckett, MD

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 years at diagnosis of brain metastases.
2. Eastern Cooperative Oncology Group (ECOG) Performance Score of <2.
3. Participants must have a biopsy-proven solid malignancy (histologic proof or unequivocal cytologic proof solid tumor malignancy from either the primary or any metastatic site) with intracranial lesions radiographically consistent with or pathologically proven to be brain metastases.
4. Patients who have undergone prior systemic therapy are eligible.
5. Life expectancy from extracranial disease greater than six months.
6. Patients with measurable brain metastasis.
7. Patients may have had prior therapy for brain metastasis, including stereotactic radiosurgery (SRS)and surgical resection. Patients must have completed prior therapy by at least 7 days prior to study enrollment for SRS and at least 14 days for surgical resection
8. If an open biopsy is performed, the patient must be at least one-week post-biopsy. This requirement is not necessary for stereotactic biopsies.
9. Creatinine clearance is ≥ 30 mL/min.
10. Start of PRDR WBRT within two weeks following registration.
11. Ability to complete the Neurocognitive Function (NCF) test battery (including people whose primary language is English).
12. Patients with previous or other malignancies whose disease is controlled and not impacting ECOG performance or life expectancy.
13. Willing and able to give consent and to comply with treatment and follow-up schedule.

Exclusion Criteria:

1. Metastases from hematological malignancy, or central nervous system malignancy.
2. Patients whose malignancy is being treated with curative intent.
3. Leptomeningeal metastases.
4. Contraindication to MRI imaging with contrast.
5. Contraindication to memantine including concurrent use of N-methyl-D-aspartate (NMDA) antagonists.
6. Stage IV-V chronic kidney disease or end-stage renal disease.
7. Participants with a maximum tumor diameter exceeding 5 cm (if not resected).
8. Prior cranial whole brain radiation therapy.
9. Past medical history of dementia which is thought to be unrelated to the brain metastases.
10. Women of childbearing potential who are known to be pregnant or are unwilling to use an acceptable method of contraception from the time of informed consent until completion of the course of radiotherapy.
11. Patients must not have a serious medical or psychiatric illness that would, in the opinion of the treating physician, prevent informed consent or completion of protocol treatment, and/or follow-up visits.
12. Non-native English speakers will be excluded since patients often lose their faculty with the language they acquired second before their native language is affected in the context of cognitive decline. This could adversely affect performance on verbal cognitive tasks.

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: WBRT-PRDR plus memantine.; Study patients will receive WBRT-PRDR within 14 days of registration. All patients will receive single daily fractions using 3D conformal radiotherapy. A dose of 30 Gy in 10 fractions will be delivered using the PRDR technique. Memantine should ideally start two days (or one day) prior to WBRT PRDR and must start no later than the fourth WBRT PRDR treatment and will continue for a maximum of 24 weeks (≈six months). Memantine will be administered as per standard institutional guidelines.

Drug: Memantine -Twice Daily or Extended Release; Both extended release memantine and twice daily memantine dosing will be allowed. Twice daily dosing: The target dose for memantine is 20 mg (10 mg divided twice daily). Dose will be escalated by 5 mg each week to a target of 10 mg twice daily (i.e., 5 mg a day on week 1, then 5 mg twice daily (BID) on week 2, then 10 mg in AM plus 5 mg in PM on week 3, followed by 10 mg in AM plus 10 mg in PM by week 4). Extended Release Memantine: The target dose for extended release memantine is 28 mg. Dose will be escalated by 7 mg per week to a target of 28 mg daily (i.e., 7 mg a day on week 1, then 14 mg a day on week 2, then 21 mg a day on week 3, followed by 28 mg a day by week 4).; Other Names: Namenda; Radiation: WBRT utilizing the PRDR technique; The total dose of 3000 cGy (30 Gy) will be divided 10 fractions of 300 cGy (3 Gy); each fraction will be delivered as a series of 20 cGy (0.2Gy) pulses separated by 3 min time intervals. 20 cGy / 3 min = 6.67 cGy/min (or 0.0667 Gy/min). Total time is determined by the fractionated series and time intervals, meaning 300cGy/20cGy = 15 division x 3 minutes = 45 minutes. Including time to set up, approximate total time per treatment session will be 60 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful completion of PRDR WBRT treatment	The number of subjects successfully completing PRDR WBRT treatment within five days of intended treatment completion.	5 days

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Michael Straza, MD, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2021
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: September 7, 2021
• First Submitted That Met QC Criteria: September 7, 2021
• First Posted (Actual): September 16, 2021

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: whole-brain radiation therapy; upfront pulsed reduced dose-rate
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Neoplasms; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Adamantane; Bridged-Ring Compounds; Amantadine; Memantine
• Other Study ID Numbers: PRO00041354

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: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No