Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT01729260

Collaborator

Accelerate Brain Cancer Cure (Other)

Enrollment

Location

Arm

96.4

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find the highest dose of mebendazole (MBZ) that can be safely given to people with malignant brain tumors in combination with the current standard of care (temozolomide) without causing severe side effects. We also want to find out if MBZ can slow the growth of the brain tumor. The study doctors have found that MBZ is effective against malignant brain tumors in the laboratory and animal models of brain tumors.

Condition or Disease	Intervention/Treatment	Phase
Newly Diagnosed High-Grade Glioma	Drug: Mebendazole	Phase 1

Detailed Description

Glioblastoma (GBM) is the most common and aggressive brain cancer, and despite significant advances in treatment the majority of patients die within two years of diagnosis. During routine animal studies we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used for pinworms, prevented tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the drug having the best results in preclinical testing 1. In GBM cell lines, mebendazole displayed cytotoxicity with IC50s ranging from 0.1-0.3 μM. Mebendazole disrupted microtubule formation in GBM cells and it's in vitro activity was correlated with reduced tubulin polymerization. In two orthotopic mouse glioma models, one syngeneic and one xenograft, mebendazole significantly extended average survival up to 63% compared to untreated controls 1.

Mebendazole is an FDA approved antiparasitic agent with a well-established side effect and safety record and was effective in our animal models in dosing schedules that are documented as safe in humans. Therefore, mebendazole is a possible anti-cancer therapeutic with pre-clinical safety and efficacy and provides a promising opportunity for a clinical trial in patients with malignant gliomas.

In addition, a recently published case report case report from the University of Michigan documented successful long term control in metastatic adrenocortical adenocarcinoma using mebendazole 2. Mebendazole was well tolerated at 200 mg/day and used as the sole treatment after the patient failed other chemotherapies.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide

Actual Study Start Date :

Apr 4, 2013

Actual Primary Completion Date :

Sep 1, 2016

Actual Study Completion Date :

Apr 16, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mebendazole All study participants will receive study drug; Mebendazole.	Drug: Mebendazole The mebendazole will be given by mouth three times every day on a 28 day cycle. it's in the form of 500 mg chewable tablets, to be taken with meals. Other Names: Brand name: Vermox

Arm

Intervention/Treatment

Experimental: Mebendazole

All study participants will receive study drug; Mebendazole.

Drug: Mebendazole

The mebendazole will be given by mouth three times every day on a 28 day cycle. it's in the form of 500 mg chewable tablets, to be taken with meals.

Other Names:

Brand name: Vermox

Outcome Measures

Primary Outcome Measures

maximum tolerated dose (MTD) of mebendazole [8 months]
To determine the maximum tolerated dose (MTD) of mebendazole in combination with temozolomide (TMZ) given after surgery and the standard radiation and TMZ treatment in patients with newly diagnosed malignant gliomas.

Secondary Outcome Measures

Overall Survival [10 years]
Overall survival in years.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have histologically confirmed newly diagnosed high-grade glioma(WHO Grade III or IV)
Age ≥18 years
Karnofsky Performance Score (KPS) ≥ 60%
Life expectancy greater than 12 weeks
Patients must have adequate organ and marrow function
Completed >80% of the prescribed radiation therapy and concurrent temozolomide according to the Stupp regimen without grade 3 or 4 hematologic toxicity
Patients may have received Gliadel during surgery
Ability to swallow pills and keep medication record
women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation.
Ability to understand and willingness to sign a written informed consent document
Be able to comply with treatment plan, study procedures and follow-up examinations

Exclusion Criteria:

Patients must not have received prior therapy other than standard chemoradiation according to Stupp et al and Gliadel.
Patients may not be receiving any other investigational agents while on study
Patients who have known allergy to mebendazole or benzimidazole
Patients who have previously had a severe side effect, such as agranulocytosis and neutropenia, in conjunction with previous mebendazole or benzimidazole class drug for a parasitic infection
Patients who are taking metronidazole and cannot be safely moved to a different antibiotic greater than 7 days prior to starting mebendazole therapy
Patients who have taken any benzimidazole (ABZ, flubendazole, thiabendazole, fenbendazole, triclabendazole, etc.) within the last 3 months
Patients who are taking any anti-convulsant medication that interferes with the cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, chronic hepatitis, acute hepatitis, or psychiatric illness/social situation that would limit compliance with study requirements
Pregnant women are excluded
Patients with human immunodeficiency virus (HIV), hepatitis B surface antigen or hepatitis C positive; or with a history of chronic active hepatitis or cirrhosis
Patients with a history of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product administration or may interfere with the interpretation of the results
Patients who are not available for follow-up assessments or unable to comply with study requirements