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Disulfiram/Copper Combination In The Treatment of Newly Diagnosed Glioblastoma Multiform (GLIODIS)

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ClinicalTrials.gov Identifier: NCT01777919
Recruitment Status : Not yet recruiting
First Posted : January 29, 2013
Last Update Posted : October 17, 2016
Sponsor:
Collaborators:
University of Ioannina
University of Eastern Finland
University of Ulm
Information provided by (Responsible Party):
Petros Karamanakos, MD, PhD, Olympion Medical Center

Tracking Information
First Submitted Date  ICMJE January 24, 2013
First Posted Date  ICMJE January 29, 2013
Last Update Posted Date October 17, 2016
Study Start Date  ICMJE January 2017
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2013)
Progression-free survival [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01777919 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2013)
Overall survival [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Disulfiram/Copper Combination In The Treatment of Newly Diagnosed Glioblastoma Multiform
Official Title  ICMJE A PHASE II CLINICAL TRIAL FOR THE EVALUATION OF THE EFFICACY OF DISULFIRAM/COPPER COMBINATION AS AN ADJUVANT AND CONCURRENT CHEMOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORM
Brief Summary

Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults. Despite maximal treatment tumor relapse occurs regularly accompanied by unfavourable prognosis. Among other reasons, it is believed that this could be in part due to the existence of the so-called tumor stem cells (TSCs), a cellular subfraction within GBM which escape therapy by being highly resistant to irradiation and chemotherapy and thus constituting the source of tumor recurrence.

GBM, like many other cancers, show a sub-population of aldehyde dehydrogenase (ALDH) overexpressing TSCs. More specifically, ALDH1A1, a cytoplasmatic isoform of ALDH, proved to be a novel stem cell marker in human GBM. In addition, ALDH1A1 has been shown to be a mediator for resistance of GBM to temozolomide (TMZ) and a reliable predictor of clinical outcome; prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels. Consequently, ALDH1A1 may serve as a potential target to improve treatment of human GBM through inhibition of the enzyme.

Disulfiram (DSF) has been used for more than sixty years in the treatment of chronic alcoholism because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver ALDHs. Actually, DSF is a strong inhibitor of ALDH1A1 and relatively non-toxic at therapeutic (for chronic alcoholism) doses that can penetrate the blood-brain barrier. In addition, DSF has been shown to be cytotoxic on GBM stem-like cells, inhibiting the growth of TMZ resistant GBM cells and blocking self-renewal by ~100% , while it has been identified as an inhibitor of human GBM stem cells in high-throughput chemical screens. Interestingly, a number of these actions were copper-dependent.

In the current Phase II clinical trial, DSF/copper combination will be tested as an adjunctive and concurrent chemotherapy in the treatment of newly diagnosed GBM. According to our hypothesis, initiation of DSF chemotherapy after the resection of the tumor and before the introduction of the standard radio-chemotherapy will inhibit ALDH1A1 of GBM TSCs making them more susceptible to radio-chemotherapy and possibly reducing the recurrence rate of GBM. On the other hand, the addition of copper will probably enhance the cytotoxic effects of DSF possibly through augmentation of its pro-apoptotic and proteasomal inhibitory actions.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE
  • Drug: Temozolomide
    Other Name: Temodar
  • Drug: Disulfiram
    Other Name: Antabuse
  • Drug: Copper
Study Arms  ICMJE Experimental: Temozolomide+Disulfiram/copper

Disulfiram/copper combination will be started on the 5th postoperative day and before the initiation of the standard radiochemotherapy (fractionated irradiation with a total dose of 60 Gy with concomitant 75 mg/m2 body surface temozolomide each day, including weekends, during irradiation). After completion of the radiation therapy patients will receive maintenance temozolomide 150-200 mg/m2 body surface on Days 1-5 every 28 days for 6 months. Daily administration of disulfiram and copper will take place for the whole study period.

NOTE: Patients may receive additional maintenance temozolomide at the discretion of the treating medical oncologist.

Interventions:
  • Drug: Temozolomide
  • Drug: Disulfiram
  • Drug: Copper
Publications * Karamanakos PN. Possible role for furazolidone in the treatment of glioblastoma multiforme. J BUON. 2013 Oct-Dec;18(4):1097.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 28, 2013)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histopathologically confirmed diagnosis of glioblastoma (World Health Organization [WHO] grade IV astrocytoma). Patients must be newly diagnosed with unifocal supratentorial GBM amenable to gross total resection (< 1 cm. enhancing rim) and not yet received chemoradiation.
  2. Patient must have undergone a gross total surgical resection of the tumor mass with post-surgical MRI (performed within 72 hours after operation) demonstration of adequacy defined as < 1.0 cm of residual enhancement away from resection cavity perimeter.
  3. Ability to start disulfiram on the 5th postoperative day
  4. ≥ 18 years of age
  5. Karnofsky Performance Status (KPS) ≥ 70%
  6. Adequate bone marrow function, defined as:

    Absolute neutrophil count ≥ 1000 cells/mm3 Hemoglobin ≥ 10 g/dL Platelet count ≥ 100,000 cells/mm3

  7. Adequate hepatic function, defined as:

    Bilirubin ≤ 2.0 mg/dL Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 4x upper limit of normal (ULN)

  8. Adequate renal function, defined blood urea nitrogen (BUN) < 30 mg/dL and creatinine < 2 mg/dL
  9. Prothrombin time (PT) and activated partial thromboplastin time (PTT) ≤ 1.6x control unless therapeutically warranted
  10. Female patients of child-bearing potential must have negative serum or urine pregnancy test
  11. If not surgically sterile, male and female patients of childbearing age must use double barrier contraception (hormonal; intrauterine device; barrier)
  12. Patient must give written informed consent prior to any study-specific procedures being implemented.

Exclusion Criteria:

  1. Recurrent disease
  2. Infratentorial or multifocal tumor.
  3. Placement of Gliadel wafer
  4. No severe, active comorbidity, including any of the following:

    • Unstable angina and/or congestive heart failure requiring hospitalization
    • Transmural myocardial infarction within the last 6 months
    • Chronic obstructive pulmonary disease
    • Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    • Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS) related illness or other serious medical illness
    • Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy
    • Known history of an autoimmune disorder
    • Presence of any other active malignancy or prior history of malignancy (except for basal cell carcinoma of the skin)
  5. Alcoholism
  6. Breastfeeding
  7. Prior or planned chemotherapy, immunotherapy, biologic therapy, radiation therapy, radioimmunotherapy, hormonal therapy, or experimental therapy for brain tumor
  8. History of severe allergic reaction to contrast media.
  9. Inability to undergo an MRI.
  10. Patients treated on any other therapeutic clinical trial within 30 days prior to study entry or during participation in the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Petros N Karamanakos, MD, PhD +30 6945 548463 pkaramanakos@olympion-sa.gr
Contact: Marios S Marselos, MD, PhD +30 6976 119554 mmarsel@cc.uoi.gr
Listed Location Countries  ICMJE Greece
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01777919
Other Study ID Numbers  ICMJE PK-18081973
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Petros Karamanakos, MD, PhD, Olympion Medical Center
Study Sponsor  ICMJE Olympion Medical Center
Collaborators  ICMJE
  • University of Ioannina
  • University of Eastern Finland
  • University of Ulm
Investigators  ICMJE
Principal Investigator: Petros N Karamanakos, MD, PhD Department of Neurosurgery, Olympion Medical Center, 26443, Patras, GREECE
PRS Account Olympion Medical Center
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP