Disulfiram/Copper With Concurrent Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

A Phase I/II Dose-escalation and Dose-expansion Study of Disulfiram/Copper With Concurrent Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

The proposed phase I/II study of disulfiram (DSF) for patients with presumed glioblastoma multiforme (GBM) based on magnetic resonance imaging (MRI) or biopsy, including administration before surgery and during adjuvant chemoradiotherapy. Patients will be treated with 3 days of preoperative DSF/copper (Cu) prior to their surgery (or biopsy), which will be followed by collection of tumor samples during surgery for analysis of drug uptake. After the surgery, patients will receive standard radiation therapy (RT) and temozolomide (TMZ) with the addition of concurrent DSF/Cu.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Drug: Temozolomide; Procedure: Surgery; Radiation: Radiation; Drug: Disulfiram; Drug: Copper Gluconate

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; 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

Description

Inclusion Criteria:

• Diagnosis of GBM or its histological variants (WHO grade IV). Patients who are participating in the optional preoperative pharmacokinetic study, may have presumed GBM based on clinical/radiological findings. However, patient must have histologically confirmed GBM before continuing to receive DSF with concurrent RT/TMZ.
• Expansion Cohort: must have a diagnosis of GBM (or its histological variants) with IDH, BRAF, or NF1 mutations. Confirmation of these mutations may be either by immunohistochemistry or next-generation sequencing
• At least 18 years of age.
• Karnofsky performance status (KPS) of at least 60%
• For patients who will participate in the optional pre-operative DSF pharmacokinetic study, they should be eligible for surgical resection for which at least 0.2 cubic cm or approximately 200 mg of tumor will be removed in additional to tumor specimen required for pathology evaluation. Patients enrolled after undergoing surgical resection or biopsy with histologically confirmed GBM are not required to meet this point of inclusion.
• Eligible for and planning to receive standard fractionated RT with concurrent TMZ.
• Willing to remain abstinent from consuming alcohol while on DSF.
• Willing to defer definitive surgery for one week while taking DSF and Cu. Patients who declined the optional pre-operative pharmacokinetic study or enrolled after undergoing surgical resection or biopsy with histologically confirmed GBM are not required to meet this point of inclusion.

• Meets the following laboratory criteria:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin > 10.0 g/dL (transfusion and/or ESA allowed)
  • Total bilirubin ≤ 2x institutional upper limit of normal (ULN)
  • AST and ALT < 3 x ULN
  • Serum creatinine < 1.5 x ULN or creatinine clearance > 50 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 treatment
• Enrolled on another clinical trial testing a novel therapy or drug.
• History of allergic reaction to DSF or Cu.
• Treatment with the following medications are contraindicated with DSF when taken within 7 days prior to the first dose of DSF + Cu: metronidazole, isoniazid, dronabinol, carbocisteine, lopinavir, paraldehyde, ritonavir, sertaline, tindazole, tixanidine, atazanavir. (Note: the following medications are not contraindicated but should be cautioned if taking concurrently with DSF: warfarin, phenytoin, theophylline, chlorzoxazone, chlordiazepoxide, diazepam. If the patient is taking warfarin, INR should be monitored closely. If the patient has to remain on phenytoin, its serum concentration and response should be monitored closely.
• Active or severe hepatic, cardiovascular, or cerebrovascular disease, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class III or IV heart failure, 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.
• History of Wilson's disease or family member with Wilson's disease.
• History of hemochromatosis or family member with hemochromatosis.
• Pregnant and breastfeeding women will be excluded because of the known teratogenic effect of RT and the unknown effect of TMZ and DSF on fetal development. 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: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram (DSF) dose level 2=250mg.; Preoperative DSF/Copper (CU) x 3 days (optional); Surgery performed per routine clinical care.; After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study).; Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions.; Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care.; DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose.; 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Drug: Temozolomide; Other Names: Temodar®; Procedure: Surgery; Radiation: Radiation; Drug: Disulfiram; Other Names: DSF; Antabuse®; Drug: Copper Gluconate; Other Names: Copper; Cu
Experimental: Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram (DSF) dose level 3=375mg.; Preoperative DSF/Copper (CU) x 3 days (optional); Surgery performed per routine clinical care.; After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study).; Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions.; Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care.; DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose.; 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Drug: Temozolomide; Other Names: Temodar®; Procedure: Surgery; Radiation: Radiation; Drug: Disulfiram; Other Names: DSF; Antabuse®; Drug: Copper Gluconate; Other Names: Copper; Cu
Experimental: Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion); Surgery performed per routine clinical care.; Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions.; Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care.; Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy.; 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.; If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Drug: Temozolomide; Other Names: Temodar®; Procedure: Surgery; Radiation: Radiation; Drug: Disulfiram; Other Names: DSF; Antabuse®; Drug: Copper Gluconate; Other Names: Copper; Cu

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of DSF (Dose-escalation Phase Only)	The maximum tolerated dose (MTD) of DSF is defined as the dose level at which 20% of the cohort experience dose-limiting toxicity (DLT) within 18 weeks from start of RT (or 12 weeks from the end of RT if there is a delay in RT). MTD is assessed from the first dose of DSF in combination with TMZ and RT; patients will not be assessed for DLT during the pre-surgery period when they are receiving the lead-in doses of DSF.; A DLT is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/TMZ which occurs within 18 weeks following the first dose of DSF with RT+TMZ (corresponding to approximately 6 weeks during RT and 12 weeks after RT)	Estimated to be 2 years and 28 weeks
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)		1 year
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)		2 years
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)		3 years
Mean Overall Survival (Dose-expansion Phase Only)		Through completion of follow-up (up to 5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.	Through completion of DSF treatment (up to 38 weeks)
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex)	Will be determined using mass spectrometer	At the time of surgery (day 4)
Mean Progression-free Survival (PFS)	Will be determined from the first day of RT to the time of tumor progression or death, whichever occurs first. Tumor progression will be determined using the RANO criteria.	Through completion of follow-up (up to 5 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Pseudo-progression (PsP)	-Pseudoprogression is defined as a transient increase of tumor after chemoradiotherapy that subsequently stabilizes without a change of therapy	Through completion of follow-up (up to 5 years)
Pharmacodynamic Studies on Glutamate Metabolism as Measured by Measurement of Glutamine Levels in Plasma and Tumor Tissues		Week 6
Pharmacodynamic Studies on Glutamate Metabolism as Measured by Measurement of Glutamate Levels in Plasma and Tumor Tissues		Week 6
Time to Tumor Progression (TTP) (Dose-escalation Phase Only)	-≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids. The absolute increase in any dimension must be at least 5mm when calculating the products; Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy not caused by comorbid events; Any new measureable lesion; Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, and so on) or changes in corticosteroid dose; Failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease	Through completion of follow-up (up to 5 years)
Pharmacodynamic Studies on Glutamate Metabolism as Measured by Measurement of Aspartate Levels in Plasma and Tumor Tissues		Week 6
Pharmacodynamic Studies on Glutamate Metabolism as Measured by Measurement of Glucose Levels in Plasma and Tumor Tissues		Week 6
Pharmacodynamic Studies on Glutamate Metabolism as Measured by Measurement of Lactate Levels in Plasma and Tumor Tissues		Week 6

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Jiayi Huang, M.D., Washington University School of Medicine

Publications and helpful links

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): June 15, 2016
• Primary Completion (Actual): May 12, 2024
• Study Completion (Actual): May 12, 2024

Study Registration Dates

• First Submitted: March 9, 2016
• First Submitted That Met QC Criteria: March 16, 2016
• First Posted (Estimated): March 22, 2016

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Trace Elements; Micronutrients; Antineoplastic Agents, Alkylating; Alkylating Agents; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Temozolomide; Copper; Disulfiram
• Other Study ID Numbers: 201604115

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: Yes
• product manufactured in and exported from the U.S.: No