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Neurocognitive Decline in Patients With Brain Metastases

Primary Purpose

Brain Metastases

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Stereotactic Radiosurgery

About this trial

This is an interventional treatment trial for Brain Metastases

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age ≥ 18 years.
ECOG Performance Score of 2 or better/Karnofsky Performance score of 50-60 or better.
Biopsy-proven non-hematopoietic malignancy, except for germ cell cancer. Small cell lung carcinoma is eligible for this study.
Six or more metastases on diagnostic or treatment planning imaging, which include either CT Brain (with contrast) or MR Brain (with or without contrast) imaging.
Largest tumor <= 4 cm.
No prior SRS to the lesions which will be treated on protocol.
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

Prior whole brain radiotherapy
Patients with leptomeningeal metastasis. (NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.)
Patients with life expectancy < 4 months.
Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Sites / Locations

University of Texas Southwestern Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Radiation

Arm Description

Stereotactic Radiosurgery

Outcomes

Primary Outcome Measures

Phase I: To determine the toxicity within 60 days from the date of SRS, in patients with a greater intracranial disease burden, defined as 6 or more metastases.

Any subject who receives treatment on this protocol will be evaluated for toxicity. Each patient will be assessed for the development of toxicity according to the study calendar. Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 5.0. The following acute (<30 days) and subacute (>30 days - <60 days) toxicities probably or definitely attributable to the protocol treatment, as defined in CTCAE v5.0, will be dose limiting toxicities (DLT) of the study. Grade 3 or higher neurologic toxicity in the below categories: Ataxia Symptomatic Central Nervous System Necrosis which is interfering with ADLs (Activities of Daily Living), or requiring treatment with hyperbaric oxygen, Avastin, or resection. Asymptomatic necrosis present on imaging alone does not constitute DLT. Cerebral Edema (Grade 4) Intracranial Hemorrhage Seizure Any Grade 4 or 5 toxicities definitely attributable to the protocol treatment.

Phase II: Determine the cognitive deterioration (HVLT delayed recall) in patients treated with SRS for multiple metastases (from baseline to 4 months)

The Hopkins Verbal Learning Test (HVLT) is a memory test that gives information about memory. Each patient will serve as her or his own control, and the relative decline in HVLT-DR (Hopkins Verbal Learning Test- Delayed Recall) score from baseline to 4 month follow-up is deﬁned as Δ HVLT-DR = (HVLT-R DR at baseline - HVLT-DR at 4 month follow up) / HVLT-DR at baseline. A positive change indicates a decline in function.

Secondary Outcome Measures

Local control

To determine the optimal dose which will provide local control in patients with a greater intracranial disease burden, defined as 6 or more metastases. Local control is defined as the time between the date of SRS and the first date of documented progressive disease of the treated lesions.

Overall survival (OS)

To determine overall survival (OS). Overall survival is defined as the time between date of SRS (Stereotactic radiosurgery) and date of death.

Full Information

NCT ID

NCT03508752

First Posted

January 22, 2018

Last Updated

March 30, 2023

Sponsor

University of Texas Southwestern Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT03508752

Brief Title

Neurocognitive Decline in Patients With Brain Metastases

Official Title

Phase I/II Trial to Determine the Neurocognitive Decline in Patients With Multiple (>6) Brain Metastases Treated With Distributed Stereotactic Radiosurgery

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 5, 2017 (Actual)

Primary Completion Date

December 31, 2023 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Texas Southwestern Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The phase I component of the study is to identify maximal tolerated dose (MTD). The phase II is to evaluate neurocognitive decline.

Detailed Description

On review of our experience with treatment for brain metastases since 2009, we have treated over 100 patients with 6 or more metastases in a single radiosurgery session. In the past year and a half (2015-16) there have been approximately 50 patients treated with six or more metastases, indicating that there has been a shift in management of intracranial metastatic disease with increasing preference for radiosurgery despite the presences of greater metastatic burden. The phase I component will accrue 7-15 patients at each dose cohort until the MTD is determined. Once the MTD is reached, the phase II component will commence with a total of 50 patients total enrolled at the MTD, with a study time of 3 years. The primary endpoint of the phase I component is toxicity. The primary endpoint of the phase II component is the change in neurocognitive function, defined by a decline in the Hopkins Verbal Learning Test- Revised delayed recall. Data from the WBRT-alone arm of the PCI-P-120-9801 phase III trial evaluating WBRT plus motexafin gadolinium demonstrated a 30% mean relative decline in the HVLT-R delayed recall score from baseline to 4 months, with a standard deviation of 41% 9,10. More recently, in patients treated with SRS alone for 1-3 metastases versus SRS plus whole brain radiotherapy, the 4-month rates of HVLT-R delayed recall deterioration were 6% and 22% for the SRS alone arm and SRS + whole brain radiotherapy arm, respectively. Given the greater intracranial burden of disease, we estimate the mean relative decline in HVLT-R delayed recall to be intermediate between SRS alone for 1-3 metastases and whole brain radiotherapy. We predict that after SRS for multiple metastases the mean relative decline in delayed recall as 15%, an improvement over the historical control of whole brain radiotherapy alone which had a mean relative decline in HVLT-R delayed recall of 30%.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain Metastases

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Radiation

Arm Type

Experimental

Arm Description

Stereotactic Radiosurgery

Intervention Type

Radiation

Intervention Name(s)

Stereotactic Radiosurgery

Intervention Description

Stereotactic Radiosurgery dose is based on the largest tumor size

Primary Outcome Measure Information:

Title

Phase I: To determine the toxicity within 60 days from the date of SRS, in patients with a greater intracranial disease burden, defined as 6 or more metastases.

Description

Time Frame

60 days

Title

Phase II: Determine the cognitive deterioration (HVLT delayed recall) in patients treated with SRS for multiple metastases (from baseline to 4 months)

Description

Time Frame

4 months

Secondary Outcome Measure Information:

Title

Local control

Description

Time Frame

90 days

Title

Overall survival (OS)

Description

To determine overall survival (OS). Overall survival is defined as the time between date of SRS (Stereotactic radiosurgery) and date of death.

Time Frame

2 years

Other Pre-specified Outcome Measures:

Title

To determine neurocognitive outcomes

Description

via HVLT (Hopkins Verbal Learning Test) and quality of life via FACT-Br (Functional Assessment of Cancer Therapy) amongst patients treated with > 6 metastases via SRS. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

To determine the time to distant brain recurrence

Description

distant brain recurrence is defined as time between date of SRS and development of new metastases. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

To determine the incidence of salvage WBRT or radiosurgery

Description

WBRT is defined as whole brain radiation therapy. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

4 months

Title

Prospectively collect and analyze histology and mutational/hormone status. This is an exploratory outcome and was added as a secondary outcome in error.

Description

Patients' disease status over time

Time Frame

3 years

Title

Prospectively collect and analyze hippocampal dose and relation to neurocognitive decline

Description

Hippocampal dose measured in cGy (centigray); neurocognitive decline assessed by HVLT (Hopkins Verbal Learning Test). This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze whole brain integral dose, V8, V10, and V12 and relation to toxicity

Description

assessed by CTCAE v5.0. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze the total treatment time

Description

Treatment time measured in hours, minutes, and seconds. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze total brain metastases volume and relation to local control, neurocognitive outcome, quality of life, and toxicity

Description

Total brain metastases volume (cc). This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze the size of treated brain metastases

Description

Measured in millimeters/centimeters. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze the number of brain metastases and relation to local control, neurocognitive outcome, quality of life, and toxicity

Description

How the number of brain metastases affects patients' health over time. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze neurologic symptoms at the time of SRS

Description

Symptoms at time of stereotactic radiosurgery. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze the effect of controlled or uncontrolled systemic disease on local control, neurocognitive outcome, quality of life and toxicity

Description

How patients are affected by systemic disease over time. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze the effect of the type of prior systemic therapy on local control, neurocognitive outcome, quality of life and toxicity

Description

Prior systemic therapy includes cytotoxic, targeted, or immune therapy. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

Prospectively collect and analyze standard patient demographics

Description

Patient demographics include age in years, performance status using ECOG (Eastern Cooperative Oncology Group)/Zubrod performance scale, and gender. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

3 years

Title

To prospectively collect treatment time of patients treated for multiple metastases

Description

reported in a routine manner at scheduled times during the trial. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

2 years

Title

To determine the incidence of development of leptomeningeal disease

Description

Leptomeningeal disease is an exclusion criteria for the study. This is an exploratory outcome and was added as a secondary outcome in error.

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 18 years. ECOG Performance Score of 2 or better/Karnofsky Performance score of 50-60 or better. Biopsy-proven non-hematopoietic malignancy, except for germ cell cancer. Small cell lung carcinoma is eligible for this study. Six or more metastases on diagnostic or treatment planning imaging, which include either CT Brain (with contrast) or MR Brain (with or without contrast) imaging. Largest tumor <= 4 cm. No prior SRS to the lesions which will be treated on protocol. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: Prior whole brain radiotherapy Patients with leptomeningeal metastasis. (NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.) Patients with life expectancy < 4 months. Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Christian Chukwuma

Phone

214-645-8525

christian.chukwuma@utsouthwestern.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Sarah Neufeld, MS

Phone

214-685-8525

Sarah.Hardee@utsouthwestern.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Zabi Wardak, MD

Organizational Affiliation

UT Southwestern Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Texas Southwestern Medical Center

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

christian Chukwuma

Phone

214-685-8525

12. IPD Sharing Statement

Plan to Share IPD

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Neurocognitive Decline in Patients With Brain Metastases

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