Bioavailability of Disulfiram and Metformin in Glioblastomas

NCT03151772 | Terminated Early Phase 1

• 1 other identifier: 1144-16
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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

Conditions

Glioblastoma

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (2)

Disulfiram

EXPERIMENTAL

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 For bioavailability purpose only, treatment is withdrawn postoperatively

Drug: Disulfiram

Metformin

EXPERIMENTAL

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 For bioavailability purpose only, treatment is withdrawn postoperatively

Drug: Metformin

Interventions

Disulfiram DRUG

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

Disulfiram

Metformin DRUG

Metformin 850 mg x 3 taken preoperatively

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A suspected glioblastoma (based on MRI) or recurrent glioblastoma undergoing surgical resection.
• Elective surgical indication
• Age 18 years or older.
• Karnofsky performance status of 60 - 100 (see attachment 3).
• Able to take oral medications.
• No known allergy to substance
• Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL

You may not qualify if:

• General
• Other likely diagnosis than glioblastoma based on MRI.
• Pregnant and/or breastfeeding.
• 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.
• Suspected significant raised intracranial pressure or other indication for emergent surgery
• Unfit for participation for any other reason judged by the including physician.
• History of uncontrolled hypertension (i.e. systolic BP \> 180 mmHg) and a diagnosis of congestive heart failure
• History of psychiatric conditions (e.g. depression, psychosis, schizophrenia) or dementia.
• History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).
• History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).
• 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
• Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).
• 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).
• Addiction to alcohol or drugs. Alcohol must be avoided.
• 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.

Sponsors & Collaborators

• Sahlgrenska University Hospital: lead

Study Sites (1)

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Disulfiram; Metformin

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Disulfides; Sulfides; Sulfur Compounds; Biguanides; Guanidines; Amidines

Study Officials

• Asgeir S Jakola, MD, PhD

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor, neurosurgeon

Model Details: 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 therapies

Study Record Dates

• First Submitted: May 9, 2017
• First Posted: May 12, 2017
• Study Start: January 29, 2018
• Primary Completion: September 24, 2020
• Study Completion: September 24, 2020
• Last Updated: September 28, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)