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INSIDE: Bioavailability of Disulfiram and Metformin in Glioblastomas

Sponsor
Sahlgrenska University Hospital, Sweden (Other)
Overall Status
Terminated
CT.gov ID
NCT03151772
Collaborator
(none)
3
Enrollment
1
Location
2
Arms
31.8
Actual Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Early Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Bioavailability study with an adaptive design (evaluation after 5 patients up to a total maximum of 20 patients in each arm). Experimental therapy not to be combined and not any comparison between therapiesBioavailability study with an adaptive design (evaluation after 5 patients up to a total maximum of 20 patients in each arm). Experimental therapy not to be combined and not any comparison between therapies
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
Drug Level and Investigation of Novel Substances Indicated Downstream Effect in Glioblastoma
Actual Study Start Date :
Jan 29, 2018
Actual Primary Completion Date :
Sep 24, 2020
Actual Study Completion Date :
Sep 24, 2020

Arms and Interventions

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 For bioavailability purpose only, treatment is withdrawn postoperatively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 For bioavailability purpose only, treatment is withdrawn postoperatively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

Outcome Measures

Primary Outcome Measures

  1. Bioavailabilty disulfiram [At time of surgery]

    Concentration of disulifram-copper complex available in glioblastoma compared to blood

  2. Bioavailabilty of metformin [At time of surgery]

    Concentration of metformin available in glioblastoma compared to blood

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Sahlgrenska University Hospital Göteborg Sweden

Sponsors and Collaborators

  • Sahlgrenska University Hospital, Sweden

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Asgeir S. Jakola, Associate professor, neurosurgeon, Sahlgrenska University Hospital, Sweden
ClinicalTrials.gov Identifier:
NCT03151772
Other Study ID Numbers:
  • 1144-16
First Posted:
May 12, 2017
Last Update Posted:
Sep 28, 2020
Last Verified:
Sep 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
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
Additional relevant MeSH terms:
Glioblastoma
Metformin
Disulfiram

Study Results

No Results Posted as of Sep 28, 2020