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Disulfiram and Copper Gluconate with Radiation Therapy and Temozolomide in Treating Patients with Newly Diagnosed Glioblastoma That Can Be Removed by Surgery

Trial Status: Active

This phase I / II trial studies the side effects and best dose of disulfiram when given together with copper gluconate, radiation therapy, and temozolomide and to see how well they work in treating patients with newly diagnosed glioblastoma that can be removed by surgery. Disulfiram may reduce tumor growth by blocking the activity necessary for tumor growth. Copper gluconate is a dietary supplement that may help disulfiram work better by making the tumor cells more sensitive to the drug. Giving disulfiram and copper gluconate together with radiation therapy and temozolomide may work better in treating patients with glioblastoma.

Inclusion Criteria

  • Diagnosis of GBM or its histological variants (World Health Organization [WHO] grade IV); patients who are participating in the optional pre-operative 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.
  • Karnofsky performance status (KPS) of at least 60%
  • For patients who will participate in the optional 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
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin > 10.0 g/dL (transfusion and/or erythropoiesis stimulating agents [ESA] allowed)
  • Total bilirubin =< 2 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (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 institutional review board (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 plus (+) Cu: metronidazole, isoniazid, dronabinol, carbocisteine, lopinavir, paraldehyde, ritonavir, sertraline, tindazole, tizanidine, 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, international normalized ratio [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; women of childbearing potential must have a negative pregnancy test within 14 days of initiation of treatment

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE
Contact: Jiayi Huang
Phone: 314-362-8516

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of disulfiram (DSF) when administered with concurrent radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). (Dose-escalation phase)

II. To evaluate the overall survival (OS) of the molecularly-defined expansion cohort of newly diagnosed GBM with IDH, BRAF, or NF1 mutations when treated with the combination of DSF/copper gluconate (Cu) plus concurrent RT and TMZ. (Dose-expansion phase)

SECONDARY OBJECTIVES:

I. To describe the toxicities of DSF when given concurrently with RT and TMZ. (Dose-escalation phase)

II. To determine intratumoral drug concentration of DSF and its metabolites in resected GBM tumor tissue. (Dose-escalation phase)

III. To determine the pharmacodynamic effect of DSF on proteasome inhibition and deoxyribonucleic acid (DNA) damage. (Dose-escalation phase)

IV. To estimate the time to tumor progression, rate of pseudo-progression (PsP), progression-free survival (PFS), and OS of GBM treated with RT, TMZ, and DSF/Cu. (Dose-escalation phase)

V. To evaluate the PFS of the molecularly-defined expansion cohort of newly diagnosed GBM with IDH, BRAF, or NF1 mutations when treated with the combination of DSF/Cu plus concurrent RT and TMZ. (Dose-expansion phase)

VI. To explore differences between IDH, BRAF, or NF1 mutations in their responses to DSF/Cu plus concurrent RT and TMZ. (Dose-expansion phase)

VII. To determine the active DSF metabolite concentration in plasma and tumor tissues. (Dose-expansion phase)

VIII. To explore the pharmacodynamics effect of DSF on glutamate metabolism in plasma and tumor tissues. (Dose-expansion phase)

OUTLINE: This is a phase I, dose-escalation study of disulfiram followed by a phase II study.

Patients undergo surgical resection of tumor. Within 4-6 weeks after surgery, patients receive temozolomide orally (PO) daily for up to 49 days and undergo radiation therapy 5 days a week for 6 weeks. Patients also receive disulfiram PO once daily (QD) and copper gluconate PO thrice daily (TID) for 6 weeks in the absence of disease progression or unacceptable toxicity.

Within 4-6 weeks after completion of radiation therapy, patients receive temozolomide PO daily on days 1-5, disulfiram PO QD on days 1-28, and copper gluconate PO TID on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then periodically for 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Jiayi Huang

  • Primary ID 201604115
  • Secondary IDs NCI-2016-00623
  • Clinicaltrials.gov ID NCT02715609