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

NCT ID: NCT02715609

Last Updated: 2025-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-15
• Study Completion Date: 2024-05-12

Brief Summary

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.

Conditions

Glioblastoma Multiforme

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

Copper Gluconate

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Radiation

Intervention Type: RADIATION

Temozolomide

Intervention Type: DRUG

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.

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

Copper Gluconate

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Radiation

Intervention Type: RADIATION

Temozolomide

Intervention Type: DRUG

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.

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

Copper Gluconate

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Radiation

Intervention Type: RADIATION

Temozolomide

Intervention Type: DRUG

Interventions

Disulfiram

Intervention Type: DRUG

Copper Gluconate

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Radiation

Intervention Type: RADIATION

Temozolomide

Intervention Type: DRUG

Other Intervention Names

DSF; Antabuse®; Copper; Cu; Temodar®

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jiayi Huang, M.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.siteman.wustl.edu

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

Other Identifiers

201604115

Identifier Type: -

Identifier Source: org_study_id