Disulfiram in Treating Patients With Glioblastoma Multiforme After Radiation Therapy With Temozolomide

A Pharmacodynamic Study of Proteasome Inhibition by Disulfiram in Patients With Glioblastoma

This clinical trial studies disulfiram in treating patients with glioblastoma multiforme (GBM) who have completed radiation therapy with temozolomide. Disulfiram may block some of the enzymes needed for tumor cell growth and improve clinical outcome in GBM patients.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Temozolomide; Drug: Disulfiram; Dietary supplement: Copper gluconate

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of histologically confirmed GBM (WHO grade IV).
• At least 18 years of age.
• ECOG performance status of at least 2.
• Has received or is in the process of completing a course of definitive radiotherapy of at least 45 Gy with concurrent temozolomide (patient may be registered before completing radiotherapy as long as it is anticipated that s/he will complete at least 45 Gy).
• Eligible for and planning to receive maintenance temozolomide after completion of definitive radiotherapy plus temozolomide.
• Willing to remain abstinent from consuming alcohol while on disulfiram.

• Meets the following laboratory criteria:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin > 9.0 g/dL (transfusion and/or ESA allowed)
  • Total bilirubin ≤ 2x institutional upper limit of normal (ULN)
  • AST and ALT < 3 x ULN
  • Calculated creatinine clearance must be > 60 mL/min (by Cockcroft-Gault)
• Females of childbearing potential (defined as a female who is non-menopausal or surgically sterilized) must be willing to use an acceptable method of birth control (i.e., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Able to take oral medication.
• Able to understand and willing to sign an IRB-approved written informed consent document (legally authorized representative permitted).

Exclusion Criteria:

• Receipt of any other investigational agents within 14 days prior to study enrollment.
• Enrolled on another clinical trial testing a novel therapy or drug.
• History of allergic reaction to disulfiram.
• Treatment with clinically significant cytochromes P450 enzyme inducers, such as phenytoin, phenobarbital, chlordiazepoxide, 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.
• Active or severe hepatic, cardiovascular, or cerebrovascular disease, including myocardial infarction within 6 months prior to enrollment, have New York Heart Association (NYHA) Class III or IV heart failure (Appendix B), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• History of idiopathic seizure disorder, psychosis or schizophrenia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of initiation of treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maintenance Temozolomide + Disulfram; Beginning 4-6 weeks after completion of radiation therapy, patients receive maintenance temozolomide 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 months. Disulfiram (dose level 0 = 500 mg PO QD or dose level 1 1000 mg PO QD) on days 1-28. Treatment repeats every 28 days for 6 courses* in the absence of disease progression or unacceptable toxicity. NOTE: *Patients may receive additional maintenance temozolomide at the discretion of the treating medical oncologist.	Drug: Temozolomide; Other Names: Temodar; Drug: Disulfiram; Other Names: Antabuse
Experimental: Maintenance Temozolomide + Disulfiarm + Copper Gluconate; Beginning 4-6 weeks after completion of radiation therapy, patients receive maintenance temozolomide 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 months, disulfiram 500 mg PO QD (dose of disulfiram determined to be the MTD) on Days 1-28, and copper gluconate 6 mg PO QD on Days 1-28. Treatment repeats every 28 days for 6 courses* in the absence of disease progression or unacceptable toxicity. NOTE: *Patients may receive additional maintenance temozolomide at the discretion of the treating medical oncologist.	Drug: Temozolomide; Other Names: Temodar; Drug: Disulfiram; Other Names: Antabuse; Dietary supplement: Copper gluconate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacological effect of disulfiram in GBM patients	Degree of proteasome inhibition in peripheral white blood cells and rate of complete inhibition in GBM patients using descriptive statistics	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local tumor control probabilities	The Kaplan-Meier product-limit method will be used.	2 years
Time to tumor progression	Modeled using the Cox proportional hazard models.	2 years

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Karamanakos PN. Possible role for furazolidone in the treatment of glioblastoma multiforme. J BUON. 2013 Oct-Dec;18(4):1097. No abstract available.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2013
• Primary Completion (Actual): November 10, 2016
• Study Completion (Actual): February 9, 2018

Study Registration Dates

• First Submitted: July 19, 2013
• First Submitted That Met QC Criteria: July 19, 2013
• First Posted (Estimate): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): July 20, 2018
• Last Update Submitted That Met QC Criteria: July 19, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Trace Elements; Micronutrients; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Copper; Temozolomide; Disulfiram
• Other Study ID Numbers: 201308038

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No