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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Disulfiram
* Drug: Copper Gluconate
* Procedure: Surgery
* Radiation: Radiation
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DSF, Cu, Surgery, RT, TMZ (dose escalation)<br>DSF (dose level (DL) 1=125mg, DL 2=250mg, DL 3=375 mg, DL 4=500mg). DSF starts at DL 2 and escalated using the Time-to-Event Continual Reassessment Method 3 day lead-in of oral DSF once daily (QD) prior to surgery (optional) 2 mg Cu gluconate 3 times daily (TID) on days when DSF is given (optional pre-surgery) 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). RT 4-6 weeks following surgery at 60 Gy in 30 daily fractions. 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 QD and Cu TID 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<br> <br> * Other names: Antabuse®;Drug: Copper Gluconate<br> <br> * Other names: Cu;Procedure: Surgery<br> <br> Radiation: Radiation<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar®;|
| Experimental: DSF, Cu, Surgery, RT, TMZ (dose expansion)<br>Surgery performed per routine clinical care. RT 4-6 weeks following surgery at 60 Gy in 30 daily fractions. 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 QD and Cu TID 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. 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<br> <br> * Other names: Antabuse®;Drug: Copper Gluconate<br> <br> * Other names: Cu;Procedure: Surgery<br> <br> Radiation: Radiation<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of the regimen (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 | 
| Overall survival (dose-expansion phase only) |  | Up to 2 years after completion of treatment (up to 138 weeks after starting treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity associated with DSF when given concurrently with radiation therapy and temozolomide as measured by the grade and frequency of adverse events (dose- escalation phase only) | 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. | Up to 30 days following completion of treatment (up to 38 weeks) | 
| Intratumoral drug uptake of DSF and its metabolites in resected GBM tissue (dose-escalation phase only) | -The ratios of intratumor concentration of DSF metabolite (ditiocarb-copper complex) relative to their corresponding plasma concentration will be determined using mass spectrometer | At the time of surgery (Day 4) | 
| Proteasome inhibition of DSF on GBM tissues (dose-escalation phase only) | -Proteasome activity of GBM tissue will be measured using fluorometric proteasome assay | At the time of surgery (Day 4) | 
| Effect of DSF on DNA breaks on GBM tissues (dose-escalation phase only) | -Amount of DNA breaks will be quantified using gamma-H2AX phosphorylation (pH2AX) assay | At the time of surgery (Day 4) | 
| 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 | Up to 2 years after completion of treatment (up to 138 weeks after starting treatment) | 
| Rate of pseudo-progression (PsP) (dose-escalation phase only) | -Pseudoprogression is defined as a transient increase of tumor after chemoradiotherapy that subsequently stabilizes without a change of therapy | Up to 2 years after completion of treatment (up to 138 weeks after starting treatment) | 
| Progression-free survival (PFS) | -≥ 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 | Up to 2 years after completion of treatment (up to 138 weeks after starting treatment) | 
| Overall survival (OS) (dose-escalation phase only) |  | Up to 2 years after completion of treatment (up to 138 weeks after starting treatment) | 
| Active DSF metabolite concentration in plasma and tumor tissues (dose-expansion phase only) |  | Week 6 | 
| Pharmacodynamic studies on glutamate metabolism as measured by measurement of glutamine levels in plasma and tumor tissues (dose-escalation phase only) |  | Week 6 | 
| Pharmacodynamic studies on glutamate metabolism as measured by measurement of glutamate levels in plasma and tumor tissues (dose-escalation phase only) |  | Week 6 | 
| Pharmacodynamic studies on glutamate metabolism as measured by measurement of aspartate levels in plasma and tumor tissues (dose escalation phase only) |  | Week 6 | 
| Pharmacodynamic studies on glutamate metabolism as measured by measurement of glucose levels in plasma and tumor tissues (dose escalation phase only) |  | Week 6 | 
| Pharmacodynamic studies on glutamate metabolism as measured by measurement of lactate levels in plasma and tumor tissues (dose escalation phase only) |  | Week 6 |