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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05045950
Recruitment Status : Recruiting
First Posted : September 16, 2021
Last Update Posted : April 13, 2022
Sponsor:
Information provided by (Responsible Party):
Lindsay Puckett, MD, Medical College of Wisconsin

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Brain Metastases Drug: Memantine -Twice Daily or Extended Release Radiation: WBRT utilizing the PRDR technique Phase 2

Detailed Description:

This is a phase II, single-arm, single-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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 17, 2021
Estimated Primary Completion Date : May 2024
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine


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 Name: 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.




Primary Outcome Measures :
  1. Controlled Oral Word Association Test (COWAT) :: The letter 1 total score at baseline. [ Time Frame: Baseline ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  2. Controlled Oral Word Association Test (COWAT) :: The letter 1 total score at four months. [ Time Frame: Four months ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  3. Controlled Oral Word Association Test (COWAT) :: The letter 2 total score at baseline. [ Time Frame: Baseline ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  4. Controlled Oral Word Association Test (COWAT) :: The letter 2 total score at four months. [ Time Frame: Four months ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  5. Controlled Oral Word Association Test (COWAT) :: The letter 3 total score at baseline. [ Time Frame: Baseline ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  6. Controlled Oral Word Association Test (COWAT) :: The letter 3 total score at four months. [ Time Frame: Four months ]
    This test requires the individual to name as many words as possible that begin with a given letter, e.g., F, A and S. Sixty seconds are allotted for each letter. Individuals cannot use proper names or numbers and cannot use words with different tenses or endings once the root word has been given.

  7. Hopkins Verbal Learning Test (HVLT-R) :: Immediate Recall, Trial 1 at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  8. HVLT-R :: Immediate Recall, Trial 1 at four months. [ Time Frame: Four months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  9. HVLT-R :: Immediate Recall, Trial 2 at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  10. HVLT-R :: Immediate Recall, Trial 2 at four months. [ Time Frame: Four months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  11. HVLT-R :: Immediate Recall, Trial 3 at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  12. HVLT-R :: Immediate Recall, Trial 3 at four months. [ Time Frame: Fourth months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  13. HVLT-R :: Immediate Recall, Total, at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  14. HVLT-R :: Immediate Recall, Total, at four months. [ Time Frame: Four months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  15. HVLT-R :: Delayed Recall at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  16. HVLT-R :: Delayed Recall at four months. [ Time Frame: Four months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  17. HVLT-R :: Delayed Recognition at baseline. [ Time Frame: Baseline ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  18. HVLT-R :: Delayed Recognition at four months. [ Time Frame: Four months ]
    A list of 12 words is read aloud to the participant after which he/she is asked to recall as many of the words as possible. This is done three times for the immediate recall section. Delayed recall occurs after a 20- to 25-min delay in which the participant is asked to recall the words from the list.

  19. Trail Making Test :: Part A time to complete (in seconds) at baseline. [ Time Frame: Baseline ]
    The participant is instructed to trace a line that connects circled numbers in consecutive order.

  20. Trail Making Test :: Part A time to complete (in seconds) at four months. [ Time Frame: Four months ]
    The participant is instructed to trace a line that connects circled numbers in consecutive order.

  21. Trail Making Test :: Part A number of errors at baseline. [ Time Frame: Baseline ]
    The participant is instructed to trace a line that connects circled numbers in consecutive order.

  22. Trail Making Test :: Part A number of errors at four months. [ Time Frame: Four months ]
    The participant is instructed to trace a line that connects circled numbers in consecutive order.

  23. Trail Making Test :: Part B time to complete (in seconds) at baseline. [ Time Frame: Baseline ]
    The participant is asked to trace a line that connects circled numbers and circled letters in consecutive order while alternating between numbers and letters (1 - A - 2 - B - 3 - C, and so on).

  24. Trail Making Test :: Part B time to complete (in seconds) at four months. [ Time Frame: Four months ]
    The participant is asked to trace a line that connects circled numbers and circled letters in consecutive order while alternating between numbers and letters (1 - A - 2 - B - 3 - C, and so on).

  25. Trail Making Test :: Part B number of errors at baseline. [ Time Frame: Baseline ]
    The participant is asked to trace a line that connects circled numbers and circled letters in consecutive order while alternating between numbers and letters (1 - A - 2 - B - 3 - C, and so on).

  26. Trail Making Test :: Part B number of errors at four months. [ Time Frame: Four months ]
    The participant is asked to trace a line that connects circled numbers and circled letters in consecutive order while alternating between numbers and letters (1 - A - 2 - B - 3 - C, and so on).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05045950


Contacts
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Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office 866-680-0505 ext 8900 cccto@mcw.edu
Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office, MS 866-680-0505 ext 8900 cccto@mcw.edu

Locations
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United States, Wisconsin
Froedtert Hospital & the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Lindsay Puckett, MD    414-805-4400    lpuckett@mcw.edu   
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Lindsay Puckett, MD Medical College of Wisconsin
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Responsible Party: Lindsay Puckett, MD, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT05045950    
Other Study ID Numbers: PRO00041354
First Posted: September 16, 2021    Key Record Dates
Last Update Posted: April 13, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Lindsay Puckett, MD, Medical College of Wisconsin:
whole-brain radiation therapy
upfront pulsed reduced dose-rate
Additional relevant MeSH terms:
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Neoplasm Metastasis
Brain Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents