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

NCT02715609 | Completed Phase 1 Results DMC FDA Drug FDA Device

• 1 other identifier: 201604115
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (3)

• 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

  Through completion of DSF treatment (up to 38 weeks)

• Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex)

  At the time of surgery (day 4)

• Mean Progression-free Survival (PFS)

  Through completion of follow-up (up to 5 years)

Other Outcomes (7)

• Rate of Pseudo-progression (PsP)

  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

Study Arms (3)

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2)

EXPERIMENTAL

* 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: Disulfiram; Drug: Copper Gluconate; Procedure: Surgery; Radiation: Radiation; Drug: Temozolomide

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3)

EXPERIMENTAL

* 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: Disulfiram; Drug: Copper Gluconate; Procedure: Surgery; Radiation: Radiation; Drug: Temozolomide

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

EXPERIMENTAL

* 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: Disulfiram; Drug: Copper Gluconate; Procedure: Surgery; Radiation: Radiation; Drug: Temozolomide

Interventions

Disulfiram DRUG

Also known as: DSF, Antabuse®

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

Copper Gluconate DRUG

Also known as: Copper, Cu

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

Surgery PROCEDURE

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

Radiation RADIATION

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

Temozolomide DRUG

Also known as: Temodar®

Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 2); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose escalation - dose level 3); Disulfiram, Copper, Surgery, Radiation therapy, Temozolomide (dose expansion)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%
• Eligible for and planning to receive standard fractionated RT with concurrent TMZ.
• Willing to remain abstinent from consuming alcohol while on DSF.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

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

MeSH Terms

Conditions

Glioblastoma

Interventions

Disulfiram; Gluconates; Copper; Surgical Procedures, Operative; Radiation; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Disulfides; Sulfides; Sulfur Compounds; Sugar Acids; Hydroxy Acids; Carbohydrates; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Physical Phenomena; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Jiayi Huang
• Organization: Washington University School of Medicine

jiayi.huang@wustl.edu

314-362-8516

Study Officials

• Jiayi Huang, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2016
• First Posted: March 22, 2016
• Study Start: June 15, 2016
• Primary Completion: May 12, 2024
• Study Completion: May 12, 2024
• Last Updated: April 10, 2025
• Results First Posted: April 10, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)