Brain (Nervous System) Cancers
Conditions
Keywords
brain and nervous system
Brief summary
This research study is for participants with glioblastoma. It can cause a tumor immunosuppression which helps myeloid cells that can stop T-cell function. Disulfiram is a drug that has been used in treating other disorders, but this study will examine if disulfiram can help make the tumor environment less immunosuppressive and reduce brain swelling when taken before surgery.
Detailed description
Glioblastoma is one of the most common brain cancers that affect adults and is very hard to treat. This is due to myeloid cells, which are special immune cells in the body that prevent the body from recognizing and attacking the tumor. Because of this, immunotherapies have not worked well in treating glioblastoma. Disulfiram may also reduce brain swelling, which may decrease or delay the need for subjects to be treated with steroids. The purpose of this study is to find out if disulfiram can help reduce immunosuppression and help prevent edema symptoms when taken 3-14 days before planned surgery.
Interventions
DRUGDisulfiram (DSF)
250 milligrams (mg) disulfiram will be given daily for 3-14 prior to operation. Participants can have the option to be treated at 500mg after initial evaluation.
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Radiographically suspected or confirmed high-grade glioma planned for surgical resection as part of standard clinical care. * Able to start disulfiram at least 3 days prior to planned surgery (treatment window 3-14 days pre-op). * In-patient status for the duration of study. * Karnofsky Performance Status (KPS) ≥70%. * Adequate organ function within 14 days prior to first dose: * ANC ≥1.5 x 10\^9/L * Platelets ≥100 x 10\^9/L * Hemoglobin ≥9 g/dL * AST/ALT ≤2.5 x ULN * Total bilirubin ≤1.5 x ULN (unless Gilbert syndrome, in which case \<5 x ULN). * Total bilirubin ≤1.5 x ULN (unless Gilbert syndrome, in which case \<5 x ULN). * Ability to understand and willingness to sign written informed consent. * Willingness to avoid alcohol and alcohol-containing products during treatment and for 14 days after last dose.
Exclusion criteria
* Any dexamethasone (or other systemic glucocorticoid for cerebral edema) administered prior to enrollment/first dose (including outpatient or ED administration). This does not include inhalers or topical steroids. * Imaging features that are atypical for high-grade glioma that have reasonable concern for competing differential diagnoses (e.g. PCNSL, tumefactive MS, etc.) * Known hypersensitivity to disulfiram or thiuram derivatives. * Active or severe hepatic disease (e.g. hepatitis, cirrhosis, known liver disease that may be exacerbated by disulfiram), or baseline liver tests above inclusion thresholds. * Current use of metronidazole or other contraindicated interacting medications. See section 6.0; medication reconciliation for the list of medications/foods. * Pregnant or breastfeeding. Pregnant women are excluded from the trial because the safety in pregnancy has not been established. Women who are breastfeeding are excluded from the trial because it is not known if disulfiram is present in breast milk. * Clinically unstable neurologic status requiring immediate steroid initiation, where delaying dexamethasone for a disulfiram trial would be unsafe (investigator judgment). * Any condition that would limit compliance with alcohol avoidance or study procedures, or that would make participation unsafe in investigator judgment. * Subjects receiving any other investigational agents. * Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled or unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Complement Immunosuppressive program | day 0, up to 14 days | Evaluate whether disulfiram given pre-operation reduces the Complement Immunosuppressive myeloid program scores vs historical controls, which will be compared using a two-sample Wilcoxon rank-sum test (primary) and a two-sample t-test on the participant-level program scores (sensitivity). Measured using scRNA-sequence data. |
| Reduction in Scavenger Immunosuppressive program | day 0, up to 14 days | Evaluate whether disulfiram given pre-operation reduces the Scavenger Immunosuppressive myeloid program scores vs historical controls, which will be compared using a two-sample Wilcoxon rank-sum test (primary) and a two-sample t-test on the participant-level program scores (sensitivity). Measured using scRNA-sequence data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants needing dexamethasone within 48 hour window | 48 hours | Change in investigator-rated edema symptom composite score from baseline to Day 2 on therapy. |
| Safety of disulfiram | 14 days | Safety is defined as the rates of adverse events experienced by participants. Adverse event severity is graded according to the NCI Common Terminology for Adverse Events (CTCAE) Version 5.0 |
| Change in Edema Symptom Composite Score (ESCS) | day 0, up to 14 days | Change in ESCS is analyzed using a Wilcoxon signed-rank test |
| Tolerability of disulfiram | 14 days | Tolerability as measured by participant toxicity rates. |
| Change in Microglial Inflammatory program scores | day 0, up to 14 days | Evaluate the change in microglial inflammatory program scores vs historical controls, which will be compared using a two-sample Wilcoxon rank-sum test (primary) and a two-sample t-test on the participant-level program scores (sensitivity). Measured using scRNA-sequence data. |
| Change in Systemic Inflammatory Program Scores | day 0, up to 14 days | Evaluate the change in systemic inflammatory program scores vs historical controls, which will be compared using a two-sample Wilcoxon rank-sum test (primary) and a two-sample t-test on the participant-level program scores (sensitivity). Measured using scRNA-sequence data. |
Countries
United States
Contacts
CONTACTTiffany Hodges, MD
PRINCIPAL_INVESTIGATORTiffany Hodges, MD
University Hospitals Cleveland Medical Center
Outcome results
None listed