Please select the eligibility criteria that correspond to the clinical trial below.
Title: DIRECT (DIsulfiram REsponse as add-on to ChemoTherapy in Recurrent) Glioblastoma: A Randomized Controlled Trial
Brief Summary: Disulfiram (Antabuse®) is a well-tolerated, cheap, generic drug that has been in use since the 1950s to treat alcoholism. There is now an increasing amount of independent preclinical data to support disulfiram as an anticancer agent. The potency of disulfiram as an anticancer agent seems strengthened by copper.

The investigators aim is to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy.


Options:
A: Inclusion Criteria:

Among other criteria, patients must meet the following conditions to be eligible for the study:

1. Age ≥18 years of age.
2. Histologic diagnosis of glioblastoma (WHO Grade IV).
3. Documented EGFRvlll positive tumor status (central lab confirmation).
4. First or second relapse of de novo glioblastoma or first diagnosis or first relapse of secondary glioblastoma.
5. Previous treatment must include surgery, conventional radiation therapy and temozolomide (TMZ).
6. Screening MRI must be obtained at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy.
7. KPS of ≥ 70%.
8. If applicable, systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or equivalent per day during the week prior to Day 1.
9. Evaluable disease in Groups 1 and 2; measurable disease in Group 2C
10. Life expectancy \> 12 weeks.
11. Patients in Group 2 and 2C must have had disease progression while receiving bevacizumab or within 2 months of treatment with bevacizumab.

Exclusion Criteria:

Among other criteria, patients who meet the following conditions are NOT eligible for the study:

1. Subjects unable to undergo an MRI with contrast.
2. History, presence, or suspicion of metastatic disease
3. Prior receipt of vaccination against EGFRvIII.
4. Any known contraindications to receipt of study drugs, including known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins.
5. Use of non-protein based investigational therapy within 14 days prior to Day 1 or use of antibody-based investigational therapy within 28 days prior to Day 1.
6. Clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment
7. Evidence of recent hemorrhage on screening MRI of the brain
8. Evidence of current drug or alcohol abuse.
9. Patients in Group 1 must not have received prior treatment with bevacizumab.
B: Inclusion Criteria:

1. First or second progression of Glioblastoma;
2. Measurable disease by RANO criteria at progression;
3. Patients ≥18 years of age;
4. Patient may have been operated for recurrence. If operated: residual and measurable disease after surgery is required;
5. Surgery completed at least 28 days before randomization;
6. An interval of at least 12 weeks between prior radiotherapy or at least 23 days from prior chemotherapy, 42 days from nitrosoureas and enrollment in this study;
7. Adequate performance, i.e."Karnofsky Performance Score" of at least 70%;
8. Adequate renal, liver, and bone marrow function according to the following criteria:

   * Absolute neutrophil count ≥1500 cells/ml,
   * Platelets ≥ 100,000 cells/ml,
   * Total bilirubin within upper limit of normal (ULN),
   * Aspartate aminotransferase (AST) ≤ 2.0 X ULN,
   * Serum creatinine level ≤ ULN or creatinine clearance ≥ 50 ml/min for patients with creatinine levels above normal limits (creatinine clearance calculated by the Cockcroft-Gault formula, see Appendix II),
   * PT, PTT (in seconds) not to be prolonged beyond \>20% of the upper limits of normal.

Exclusion Criteria:

1. Prior anti-angiogenic therapy including VEGF sequestering agents (i.e. bevacizumab, aflibercept, etc.) or VEGFR inhibitors (cedirinib, pazopanib, sunitinib, sorafenib, etc.);
2. Prior stereotactic radiotherapy;
3. Pregnant or breastfeeding patients;
4. Concomitant medication that may interfere with study results; e.g. immunosuppressive agents other than corticosteroids;
5. Active infection;
6. Evidence of significant CNS haemorrhage i.e. CTCAE grade 2 or above;
7. Expected to have surgery during study period;
8. Patients with active vascular disease, either myocardial or peripheral (i.e. acute coronary syndrome, cerebral stroke, transient ischemic attack or arterial thrombosis or symptomatic peripheral vascular disease within the past 3 months);
9. Patients with known proliferative and/or vascular retinopathy;
10. Patients with known liver disease (alcoholic, drug/toxin induced, genetic, or autoimmune);
11. Patients with known active second malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Patients are not considered to have a currently active malignancy if they have completed anticancer therapy and have been disease free for greater than 2 years prior to screening;
12. Patients testing positive to one of the following viruses: HIV, HBV and HCV within the last 6 months;
13. Patients that have undergone major surgery within the last 4 weeks before enrollment;
14. Patients who have received treatment with any other investigational agent within 4 weeks before enrollment.
C: Inclusion Criteria:

* Patients 18 years or older with KPS \> 60, with life expectancy of \> 8 weeks with radiographically proven recurrent, intracranial Glioblastoma multiforme or Gliosarcoma; patients must have documentation of Rb positive disease.
* All patients must sign an informed consent and must have signed an authorization for the release of their protected health information.
* Patients must have had prior external beam radiation and temozolomide chemotherapy; there is no limit to the number of prior chemotherapies used; patients may be treated in their first, second or third relapse
* Patients must have recovered from the toxic effects of prior therapy
* Patients must have adequate bone marrow function and renal function before starting therapy. A pre-study EKG with a normal QT interval is required for all patients
* Patients must have shown unequivocal evidence for tumor progression by MRI scan and on a steroid dose that has been stable for at least 7 days.
* Patients must have an interval of greater than or equal to 42 days from the completion of radiation therapy to study entry.
* A subset of 15 patients will be enrolled prior to a planned, indicated surgical resection. Patients can be enrolled pre-operatively only if they are surgical candidates, do not have evidence of an acute intracranial hemorrhage and are able to start protocol treatment in a window of 7 days before surgery.
* Male and female patients with reproductive potential must use an approved contraceptive method. Women of childbearing potential must have a negative beta-HCG pregnancy test
* Blocks or slides of tumor tissue from a previous surgery must be available to do IHC Rb staining. Patients with negative tumors (Rb negative) will be excluded from the study.

Exclusion Criteria:

* Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
* Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
* Patients on enzyme-inducing anti-epileptic drugs or other drugs that cause CYP3A enzyme induction or inhibition will not be eligible
D: Inclusion Criteria:

1. A previous diagnosis of glioblastoma (histologically verified) and presenting with a first progression/recurrence documented by MRI.
2. Indication for treatment with chemotherapeutic alkylating agents (i.e. temozolomide OR lomustine including PCV treatment).
3. Age 18 years or older.
4. Karnofsky performance status of 60 - 100 .
5. Not receiving another experimental treatment for glioblastoma at the moment of inclusion or during active treatment within the assigned group (i.e. control or disulfiram group).
6. Able to take oral medications.
7. No known allergy to disulfiram or copper.
8. Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL
9. Serum/plasma copper and serum ceruloplasmin within institutional limits.

   a. However increased levels are seen together with ongoing acute phase reaction as determined by elevated C-reactive protein (ceruloplasmin is elevated as part of the same process) it is possible to retest after normalization of C-reactive protein.
10. Willing to refrain from ingestion of alcoholic beverages while on the study is a criteria to be randomized. However, once randomized alcohol abstinence only affects the group treated with disulfiram, and in this group it includes the entire period and one month after last dosage of disulfiram.

Exclusion Criteria:

1. Earlier treatment for progression (e.g. "rescue therapy")
2. History of idiopathic seizure disorder, psychosis or schizophrenia.
3. History of uncontrolled hypertension (i.e. systolic BP \> 180 mmHg) and a diagnosis of congestive heart failure
4. Received radiotherapy within the 3 months before the diagnosis of progression .
5. Addiction to alcohol or drugs.
6. Pregnant and/or breastfeeding.
7. Women of childbearing potential who do not have negative pregnancy test not older than 14 days before enrollment.
8. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology or toxic hepatitis or inadequate hepatic function, defined as baseline ASAT and ALAT \> 2.5 X upper institutional limit and/or bilirubin \> 2.0 X upper institutional limit.
9. History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).
10. History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).
11. Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients).
12. Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).
13. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives (phenytoin, phenobarbital, chlordiazepoxide, imipramine, diazepam, isoniazid, metronidazole, warfarin, amitriptyline within 14 days prior to the first dose of disulfiram. Of note, lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with disulfiram).
14. Unfit for participation for any other reason judged by the including physician.

Answer: D