Bioavailability of Disulfiram and Metformin in Glioblastomas (INSIDE)

Drug Level and Investigation of Novel Substances Indicated Downstream Effect in Glioblastoma

Neuro-oncological trials may fail due to the drug never getting to the intended target (i.e. within the tumor micro environment). Also, changes' occurring in tumor cells when removed from patients and grown in-vitro is another limiting factor influencing the clinical success.

Important questions are therefore:

1. Does the drug get there?
2. Does the drug do what it is intended to do?

To improve chances of clinical success there is a need for rational and intelligent selection of potential drugs in future trials. This is an initiative for analyzing tumor concentration of preoperative administered repurposed drugs

Study Overview

• Status: Terminated
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Disulfiram; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Göteborg, Sweden
    • Sahlgrenska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

The subjects must fulfill all the following inclusion criteria to be eligible for participation in the study, unless otherwise specified:

1. A suspected glioblastoma (based on MRI) or recurrent glioblastoma undergoing surgical resection.
2. Elective surgical indication
3. Age 18 years or older.
4. Karnofsky performance status of 60 - 100 (see attachment 3).
5. Not receiving another experimental treatment for glioblastoma at the moment of inclusion.
6. Able to take oral medications.
7. No known allergy to substance
8. Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL

Exclusion Criteria:

General

1. Other likely diagnosis than glioblastoma based on MRI.
2. Pregnant and/or breastfeeding.
3. Women of childbearing potential who do not have a negative pregnancy test (not older than 14 days) before inclusion.
4. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology or toxic hepatitis or inadequate hepatic function, defined as baseline ASAT and ALAT > 1.5 X upper institutional limit and/or bilirubin > 1.5 X upper institutional limit.
5. Suspected significant raised intracranial pressure or other indication for emergent surgery
6. Unfit for participation for any other reason judged by the including physician.

Specific additional exclusions criteria for disulfiram

1. History of uncontrolled hypertension (i.e. systolic BP > 180 mmHg) and a diagnosis of congestive heart failure
2. History of psychiatric conditions (e.g. depression, psychosis, schizophrenia) or dementia.
3. History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).
4. History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).
5. Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients).7
6. Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).
7. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives (phenytoin, phenobarbital, chlordiazepoxide, imipramine, diazepam, isoniazid, metronidazole, warfarin, amitriptyline within 14 days prior to the first dose of disulfiram. Of note, lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with disulfiram).
8. Addiction to alcohol or drugs. Alcohol must be avoided.
9. Serum/plasma copper and serum ceruloplasmin outside institutional limits. a. However increased levels are seen together with ongoing acute phase reaction as determined by elevated C-reactive protein (ceruloplasmin is elevated as part of the same process) it is possible to retest after normalization of C-reactive protein.

Specific additional exclusions criteria for metformin

1. Diabetic patients or other patients where treating physician and/or anesthesiologist consider may have an increased risk for lactic acidosis per- and postoperatively
2. Known renal failure, renal risk factors (including single kidney, donor kidney, polycystic kidneys) or estimated glomerular filtration rate below 80 ml/min.
3. Congestive heart failure
4. Scheduled diagnostic work-up where contrast medium containing iodine is indicated
5. Concomitant use of NSAIDs (risk of renal injury)
6. Risk of dehydration judged by the treating physician (e.g. when symptoms include vomiting)
7. Alcohol must be avoidance during treatment (increased risk of lactic acidosis)
8. Treatment with diuretics as they may increase risk of lactic acidosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Disulfiram; Disulfiram 200 mg twice daily and copper 2,5 mg once daily. For bioavailability purpose only, treatment is withdrawn postoperatively	Drug: Disulfiram; 200 mg disulfiram two times daily and 2,5 mg copper once daily taken preoperatively
Experimental: Metformin; Metformin 850 mg x 3 daily. For bioavailability purpose only, treatment is withdrawn postoperatively	Drug: Metformin; Metformin 850 mg x 3 taken preoperatively

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bioavailabilty disulfiram	Concentration of disulifram-copper complex available in glioblastoma compared to blood	At time of surgery
Bioavailabilty of metformin	Concentration of metformin available in glioblastoma compared to blood	At time of surgery

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Investigators: Principal Investigator: Asgeir S Jakola, MD, PhD, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Actual): September 24, 2020
• Study Completion (Actual): September 24, 2020

Study Registration Dates

• First Submitted: May 9, 2017
• First Submitted That Met QC Criteria: May 10, 2017
• First Posted (Actual): May 12, 2017

Study Record Updates

• Last Update Posted (Actual): September 28, 2020
• Last Update Submitted That Met QC Criteria: September 24, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Metformin; Disulfiram
• Other Study ID Numbers: 1144-16

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No