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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified November 2013 by Olympion Medical Center
Sponsor:
Collaborators:
University of Ioannina
University of Patras
University of Athens
Information provided by (Responsible Party):
Petros Karamanakos, MD, PhD, Olympion Medical Center
ClinicalTrials.gov Identifier:
NCT01777919
First received: January 24, 2013
Last updated: November 14, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Glioblastoma Multiforme
Drug: Temozolomide
Drug: Disulfiram
Drug: Copper
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A PHASE II CLINICAL TRIAL FOR THE EVALUATION OF THE EFFICACY OF DISULFIRAM/COPPER COMBINATION AS AN ADJUNCTIVE AND CONCURRENT CHEMOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORM

Resource links provided by NLM:


Further study details as provided by Olympion Medical Center:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: March 2014
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: Temozolomide
Other Name: Temodar
Drug: Disulfiram
Other Name: Antabuse
Drug: Copper

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01777919

Contacts
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

Locations
Greece
Olympion Medical Center Not yet recruiting
Patras, Greece, 26443
Contact: Petros N Karamanakos, MD, PhD         
Principal Investigator: Petros N Karamanakos, MD, PhD         
Sponsors and Collaborators
Olympion Medical Center
University of Ioannina
University of Patras
University of Athens
Investigators
Principal Investigator: Petros N Karamanakos, MD, PhD Department of Neurosurgery, Olympion Medical Center, 26443, Patras, GREECE
  More Information

No publications provided by Olympion Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Petros Karamanakos, MD, PhD, Neurosurgeon, MD, PhD, Olympion Medical Center
ClinicalTrials.gov Identifier: NCT01777919     History of Changes
Obsolete Identifiers: NCT01982370
Other Study ID Numbers: PK-18081973
Study First Received: January 24, 2013
Last Updated: November 14, 2013
Health Authority: Greece: National Organization of Medicines

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Copper
Disulfiram
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Alcohol Deterrents
Central Nervous System Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 16, 2014