Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide

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.

Inclusion Criteria:

1. Patients must have histologically confirmed newly diagnosed high-grade glioma(WHO
Grade III or IV)

2. Age ≥18 years

3. Karnofsky Performance Score (KPS) ≥ 60%

4. Life expectancy greater than 12 weeks

5. Patients must have adequate organ and marrow function

6. Completed >80% of the prescribed radiation therapy and concurrent temozolomide
according to the Stupp regimen without grade 3 or 4 hematologic toxicity

7. Patients may have received Gliadel during surgery

8. Ability to swallow pills and keep medication record

9. 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.

10. Ability to understand and willingness to sign a written informed consent document

11. Be able to comply with treatment plan, study procedures and follow-up examinations

Exclusion Criteria:

1. Patients must not have received prior therapy other than standard chemoradiation
according to Stupp et al and Gliadel.

2. Patients may not be receiving any other investigational agents while on study

3. Patients who have known allergy to mebendazole or benzimidazole

4. 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

5. Patients who are taking metronidazole and cannot be safely moved to a different
antibiotic greater than 7 days prior to starting mebendazole therapy

6. Patients who have taken any benzimidazole (ABZ, flubendazole, thiabendazole,
fenbendazole, triclabendazole, etc.) within the last 3 months

7. Patients who are taking any anti-convulsant medication that interferes with the
cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.)

8. 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

9. Pregnant women are excluded

10. Patients with human immunodeficiency virus (HIV), hepatitis B surface antigen or
hepatitis C positive; or with a history of chronic active hepatitis or cirrhosis

11. 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

12. Patients who are not available for follow-up assessments or unable to comply with
study requirements