Glioblastoma, Glioblastoma Multiforme
Conditions
Keywords
Glioblastoma, Glioblastoma Multiforme, Anaplastic Glioma, Unmethylated
Brief summary
One of Disulfiram antitumor effects suggested in preclinical studies is MGMT (methyl-guanine-methyl-transferase) inhibition. Disulfiram MGMT inhibitory effect is enhanced by addition of Copper. This study evaluates the impact of Disulfiram (DSF) + Copper (Cu) combination when added to standard Temozolomide in the treatment of unmethylated Glioblastoma Multiforme (GBM) patients.
Detailed description
Glioblastoma is the most common malignant primary brain tumor and one of the most devastating cancers. The current standard of care for glioblastoma includes maximal safe resection followed by radiotherapy and temozolomide, which results in a median progression-free survival of less than 7 months, and median overall survival (OS) of less than 15 months. Moreover, patients with unmethylated glioblastoma respond poorly to this current standard treatment. This clinical trial evaluates the potential role of continuous, upfront use of Disulfiram in combination with Copper gluconate in enhancing temozolomide effect in the treatment of unmethylated Glioblastoma multiforme (GBM) patients.
Interventions
DRUGDisulfiram
Disulfiram is taken orally, twice daily.
DIETARY_SUPPLEMENTCopper gluconate
Copper gluconate is taken orally, twice daily
DRUGTemozolomide
Temozolomide is taken once daily
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
NA
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 or older * Diagnosis of histologically confirmed glioblastoma (WHO grade IV). Subjects with an original histologic diagnosis of low grade glioma or anaplastic glioma (WHO grade II or III) are eligible if a subsequent histological diagnosis of glioblastoma is made * Patients whose tumor is determined to be unmethylated * Patients with incomplete resection as determined by residual, measurable gadolinium or contrast-enhancing lesion or lesions * Recent resection of glioblastoma within 4 weeks of study entry. Patients who have only had a tumor biopsy and who are considered unresectable are eligible (but based on the study accrual this subset of patients with unresectable tumor may be considered for separate analysis) * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤ 2 (see appendix A) * Willing to remain abstinent from consuming alcohol while on DSF * No prior radiation or chemotherapy * Meets the following laboratory criteria: * Absolute neutrophil count ≥ 1,500/mcL (microliter) * Platelets ≥ 100,000/mcL * Hemoglobin \> 10.0 g/dL (grams/deciliter) (transfusion and/or ESA (erythropoiesis-stimulating agent) allowed) * Total bilirubin and alkaline phosphatase ≤ 2x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN * Blood urea nitrogen (BUN) and creatinine \< 1.5 x ULN * Able to take oral medication * Able to understand and willing to sign an institutional review board (IRB)-approved written informed consent document (legally authorized representative permitted)
Exclusion criteria
* Radiographic evidence of leptomeningeal dissemination, extensive intraparenchymal dissemination, infratentorial tumor, or metastatic disease to sites remote from the supratentorial brain * Enrolled in another clinical trial testing a novel therapy or drug * Received prior radiation therapy or chemotherapy for glioblastoma * History of allergic reaction/hypersensitivity to DSF (without alcohol) or copper. * Treatment with the following medications that may interfere with metabolism of DSF: warfarin (unless otherwise chosen by the study PI who will actively adjust Coumadin dose to consistently maintain a safe, therapeutic international normalized ratio (INR) \< 3, theophylline, amitriptyline, isoniazid, metronidazole, phenytoin, phenobarbital, chlorzoxazone, halothane, imipramine, chlordiazepoxide, diazepam. (Note: lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with DSF). * Active severe hepatic or renal disease * Grade 2 or higher peripheral neuropathy or ataxia per NCI CTCAE version 4.0 (2009) * History of idiopathic seizure disorder schizophrenia, or psychosis unrelated to glioblastoma, corticosteroid, or anti-epileptic medications * History of Wilson's or Gilbert's disease * Current excessive use of alcohol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Months Progression Free Survival (PFS) | 6 months | To determine 6 month PFS of patients with unmethylated glioblastoma treated with DSF-Cu in combination with concurrent radiation and temozolomide. This was assessed by the number of participants who did not have disease progression and were alive at 6 months. |
| Overall Survival | 1 and 2 years | Overall Survival will be assessed as a number of participants alive at 1 and 2 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life (QOL) | 1 year | Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire |
Countries
United States
Participant flow
Recruitment details
First subject enrollment 28th March 2018. Subjects screened at neuro-oncology MDCC (Multi-disciplinary cancer clinic) and enrolled at neuro-oncology clinic. Study closed 13th January 2022.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Open-Label, Single Arm Study to Evaluate the Safety, Tolerability, and Efficacy of Disulfiram and Copper Gluconate When Added to Standard Temozolomide Treatment in Patients with Newly Diagnosed Resected Unmethylated Glioblastoma Multiforme.
DSF will be given at 125 mg (half of a 250 mg capsule) two times daily with meals. Cu gluconate will be taken with each dose of DSF at a dose of 2 mg (one capsule/tablet). The DSF total daily dose will be 250 mg per day, as lower dose may be associated with a higher MGMT inhibitory effect. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Screen fail | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Open Label |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 15 |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 1 / 13 |
Outcome results
Primary
6 Months Progression Free Survival (PFS)
To determine 6 month PFS of patients with unmethylated glioblastoma treated with DSF-Cu in combination with concurrent radiation and temozolomide. This was assessed by the number of participants who did not have disease progression and were alive at 6 months.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label | 6 Months Progression Free Survival (PFS) | 1 Participants |
Primary
Overall Survival
Overall Survival will be assessed as a number of participants alive at 1 and 2 years.
Time frame: 1 and 2 years
Population: 2 participants are not included here because 1 was a screen fail and 1 withdrew before starting treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label | Overall Survival | 1 Year | 9 Participants |
| Open Label | Overall Survival | 2 Years | 2 Participants |
Secondary
Quality of Life (QOL)
Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire
Time frame: 1 year
Population: Disease progression or required dose modification from all participants took them all off the study. No data was collected.