Clinical trial NCT03508752: 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
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Brain Metastases
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2018-04-26
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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%.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years.
2. ECOG Performance Score of 2 or better/Karnofsky Performance score of 50-60 or better.
3. Biopsy-proven non-hematopoietic malignancy, except for germ cell cancer. Small cell lung carcinoma is eligible for this study.
4. 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.
5. Largest tumor \<= 4 cm.
6. No prior SRS to the lesions which will be treated on protocol.
7. 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).
8. Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

1. Prior whole brain radiotherapy
2. 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.)
3. Patients with life expectancy \< 4 months.
4. Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
5. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Primary outcomes:
measure: 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.
timeFrame: 60 days
measure: Phase II: Determine the cognitive deterioration (HVLT delayed recall) in patients treated with SRS for multiple metastases (from baseline to 4 months)
timeFrame: 4 months
Secondary outcomes:
measure: Local control
timeFrame: 90 days
measure: Overall survival (OS)
timeFrame: 2 years
Other outcomes:
measure: To determine neurocognitive outcomes
timeFrame: 3 years
measure: To determine the time to distant brain recurrence
timeFrame: 3 years
measure: To determine the incidence of salvage WBRT or radiosurgery
timeFrame: 4 months
measure: Prospectively collect and analyze histology and mutational/hormone status. This is an exploratory outcome and was added as a secondary outcome in error.
timeFrame: 3 years
measure: Prospectively collect and analyze hippocampal dose and relation to neurocognitive decline
timeFrame: 3 years
measure: Prospectively collect and analyze whole brain integral dose, V8, V10, and V12 and relation to toxicity
timeFrame: 3 years
measure: Prospectively collect and analyze the total treatment time
timeFrame: 3 years
measure: Prospectively collect and analyze total brain metastases volume and relation to local control, neurocognitive outcome, quality of life, and toxicity
timeFrame: 3 years
measure: Prospectively collect and analyze the size of treated brain metastases
timeFrame: 3 years
measure: Prospectively collect and analyze the number of brain metastases and relation to local control, neurocognitive outcome, quality of life, and toxicity
timeFrame: 3 years
measure: Prospectively collect and analyze neurologic symptoms at the time of SRS
timeFrame: 3 years
measure: Prospectively collect and analyze the effect of controlled or uncontrolled systemic disease on local control, neurocognitive outcome, quality of life and toxicity
timeFrame: 3 years
measure: Prospectively collect and analyze the effect of the type of prior systemic therapy on local control, neurocognitive outcome, quality of life and toxicity
timeFrame: 3 years
measure: Prospectively collect and analyze standard patient demographics
timeFrame: 3 years
measure: To prospectively collect treatment time of patients treated for multiple metastases
timeFrame: 2 years
measure: To determine the incidence of development of leptomeningeal disease
timeFrame: 2 years
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Zabi Wardak, MD
role: PRINCIPAL_INVESTIGATOR
References: