Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study of Temozolomide and Short-Course Radiation Versus Short-Course Radiation Alone In The Treatment of Newly Diagnosed Glioblastoma Multiforme in Elderly Patients
Brief Summary: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether radiation therapy and temozolomide are more effective than radiation therapy alone in treating glioblastoma multiforme.

PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared with radiation therapy alone in treating patients with newly diagnosed glioblastoma multiforme.


Options:
A: Inclusion Criteria:

* Confirmation of recurrent glioblastoma
* Life expectancy ≥ 12 weeks
* Received only one prior systemic chemotherapy regimen and this regimen must contain temozolomide

Exclusion Criteria:

* Patients on enzyme-inducing anti-epileptic drugs within 3 weeks prior to randomisation
* Poorly controlled hypertension
* Previous anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) therapy
B: Inclusion Criteria:

* Male or female ≥ 18 years of age
* Histologically confirmed de novo glioblastoma multiforme (grade IV)
* First recurrence after adjuvant treatment (surgery followed by radiotherapy and temozolomide chemotherapy with or without bevacizumab) in patients who have not received further therapeutic interventions
* For patients not undergoing a second surgery at the time of relapse, recurrent disease must include at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on an MRI scan done within 2 weeks prior to randomization
* Documented progression of disease as defined by RANO criteria at least 12 weeks after completion of radiotherapy, unless the recurrence is outside the radiation field or has been histologically documented
* Have adequate bone marrow function, liver function, and renal function, as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:

  * Hemoglobin \>9.0 g/dl
  * Absolute neutrophil count (ANC) \>1500/mm3 without transfusions or granulocyte colony stimulating factor and other hematopoietic growth factors
  * Platelet count ≥100,000/μl
  * White blood cell count (WBC) \>3.0 x 109/L
  * Total bilirubin \<1.5 times the upper limit of normal
  * ALT and AST \<3 x upper limit of normal (\<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
  * Serum creatinine \<1.5 x upper limit of normal
  * Alkaline phosphatase \<2.5 x ULN (\<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
  * PT-INR/PTT \<1.5 x upper limit of normal (Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists per medical history)
  * Lipase ≤ 1.5 x the ULN
* Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
* Analyses of MGMT methylation status on tumoral tissue at first surgery (at own institution)
* Understand, be willing to give consent, and sign the written informed consent form (ICF) prior to undergoing any study-specific procedure
* If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment
* If female and of childbearing potential, or if male, agree to use adequate contraception (eg, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug
* World Health Organization (WHO) Performance status ≤ 1 (or Karnofsky performance status (KPS) ≥70)) within 14 days prior to the initiation of study treatment
* Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
* Patients may have undergone surgery for the recurrence; the histological report must document a glioblastoma recurrence. If operated:

  * at least 28 days and maximum 42 days interval from the surgery is required prior to administration of study drugs and patients should have fully recovered
  * Exclusion Criteria:
* Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort)
* Radiotherapy within 12 weeks prior to the diagnosis of progression, if the lesion is in the radiation field,
* Have had systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation of study treatment
* Positioning of carmustin wafers during first or second surgery
* Other active or inactive malignancy (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma). Malignancy will be considered inactive if patients are in complete remission for at least 3 years prior to study entry
* Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor
* Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment
* Are pregnant
* Are breastfeeding
* Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed)
* Have congestive heart failure classified as New York Heart Association Class 2 or higher
* Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3 months prior to screening.
* Have had a myocardial infarction \< 6 months prior to initiation of study treatment
* Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
* Have uncontrolled hypertension (systolic blood pressure \[SBP\] \> 140 mmHg or diastolic blood pressure \[DBP\] \> 90 mmHg) despite optimal medical management
* Have had arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months prior to the initiation of study treatment
* Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0)
* Have a known history of human immunodeficiency virus infection
* Have either active or chronic hepatitis B or C requiring treatment with antiviral therapy
* Have a history of organ allograft
* Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity
* Have had a hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment
* Have a non-healing wound, ulcer, or bone fracture
* Have renal failure requiring hemodialysis or peritoneal dialysis
* Have dehydration ≥ Grade 1 (NCI-CTCAE v 4.0)
* Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained
* Have persistent proteinuria \> 3.5 g/24 hours measured by urine protein creatinine ratio from a random urine sample (Grade 3, NCI-CTCAE v 4.0)
* Have any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
* Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
* Have any malabsorption condition
* Recurrent disease located outside of the brain
C: 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.
D: DISEASE CHARACTERISTICS:

* Histopathologically confirmed glioblastoma multiforme

  * Grade IV disease by WHO classification
  * Newly diagnosed disease
* Initial diagnostic surgery or biopsy performed within the past 4 weeks
* Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Absolute granulocyte count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* ALT and AST \< 2.5 times ULN
* No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide
* No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
* No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment
* No other condition (e.g., psychological or geographical) that would preclude study compliance

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy
* No prior radiotherapy
* No prior or concurrent investigational therapy
* No concurrent surgical procedures for tumor debulking
* No concurrent stereotactic boost radiotherapy
* No other concurrent chemotherapy, immunotherapy, or biological therapy
* No concurrent epoetin alfa
* Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days

Answer: D