Bioavailability of Disulfiram and Metformin in Glioblastomas

NCT ID: NCT03151772

Last Updated: 2020-09-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-29
• Study Completion Date: 2020-09-24

Brief Summary

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

Conditions

Glioblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Disulfiram

Disulfiram 200 mg twice daily and copper 2,5 mg once daily. For bioavailability purpose only, treatment is withdrawn postoperatively

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

200 mg disulfiram two times daily and 2,5 mg copper once daily taken preoperatively

Metformin

Metformin 850 mg x 3 daily. For bioavailability purpose only, treatment is withdrawn postoperatively

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin 850 mg x 3 taken preoperatively

Interventions

Disulfiram

200 mg disulfiram two times daily and 2,5 mg copper once daily taken preoperatively

Intervention Type: DRUG

Metformin

Metformin 850 mg x 3 taken preoperatively

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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.

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

Sponsors

Sahlgrenska University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Asgeir S. Jakola

Associate professor, neurosurgeon

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Asgeir S Jakola, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Sahlgrenska University Hospital

Locations

Sahlgrenska University Hospital

Gothenburg, , Sweden

Countries

Sweden

Other Identifiers

1144-16

Identifier Type: -

Identifier Source: org_study_id