Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors

The primary objectives of this study are to determine the maximum tolerated dose (MTD) of
oral mebendazole in patients with recurrent/progressive pediatric brain tumors and to confirm
the tolerance of the MTD of oral mebendazole by assessing tolerance in a dose expansion
cohort. Secondary Objectives of the study include to determine the safety, tolerability and
toxicity of mebendazole in this patient population, determine the plasma levels of
mebendazole in this patient population and Determine progression-free and overall survival of
mebendazole in an extended cohort of patients with treatment refractory pediatric brain
cancer.

Mebendazole (MBZ) is a drug developed to treat human helminthic disease and is FDA-approved
for the treatment of roundworm, common hookworm, American hookworm, pinworm and whipworm. MBZ
use is well documented and frequently used in tropical countries at higher doses for the
rarer parasitic infections of the brain.

We have shown efficacy in preclinical laboratory models of high grade glioma and
medulloblastoma. Mebendazole therapy demonstrated safety in a phase I clinical trial for
adults with high grade gliomas such as glioblastoma. This trial completed the maximum
approved enrollment of 24 patients treated with mebendazole, with high doses consistent with
dosing published for severe parasitic infections.

Laboratory studies indicate that mebendazole enters the brain and brain tumors at
concentrations that may be effective for a combination of anti-cancer mechanisms. In animal
models of brain cancer evidence suggest that mebendazole can prevent cell proliferation by
interfering with tubulin formation, and it may prevent the formation of new abnormal blood
vessels that feed tumor growth.

The patients for this experimental trial are those between the age of 1 to 21 with the
diagnosis of medulloblastoma, or high grade glioma, where the tumor has resumed growth or
continued to grow despite standard medical therapy. High grade glioma are those with a World
Health Organization (WHO) grade of III or IV. It includes diagnosis of pediatric
glioblastoma, anaplastic astrocytoma, and diffuse intrinsic pontine glioma. Patients who have
failed other forms of experimental therapy may also be eligible for this trial.

Mebendazole is provided at no cost in the form of a chewable 500 mg tablets, recommended to
be taken three times daily with meals or food. The pill can be chewed after meals, or ground
up to be mixed with food or drink. It has a mild orange flavor that is similar in consistency
to an antacid tablet.

Although side effects are rare and the vast majority are reversible, they include stomach
upset, decreased blood count, and elevated liver enzymes due to inflammation.

The main additional procedure beyond taking this drug, is that patients are requested to
consent to up to three additional blood draws to check the blood (serum) levels of the drug
to ensure it is being absorbed at sufficient doses.

Patients can continue to receive the drug as long as in the attending physicians opinion the
therapy is not causing any severe side effects, and there is no clear indication that the
patient will not respond to mebendazole therapy. Patients can withdraw from this trial at any
time for any reason, and may be eligible for other experimental therapies afterwards.

Inclusion Criteria:

1. Patients must have a confirmed recurrent/progressive brain malignancy that have failed
at least one prior treatment regimen.

2. Age for inclusion in this trial at time of patient enrollment is ≥ 1 year, and up to
21 years (prior to the 22nd birthday) with any of the recurrent medulloblastoma or
recurrent high grade glioma may be consented and treated under this protocol. Patients
who turn 22 during the course of the trial will continue to be treated.

3. Karnofsky Performance Score (KPS) > 50% for patients ≥10 years of age. Lansky score of
≥ 50 for children < 10 years of age.

4. Life expectancy greater than 10 weeks.

5. Patients must have adequate organ and marrow function as defined below:

- Leukocytes ≥ 3,000 cells per microliter

- Absolute Neutrophil Count ≥ 750 cells per microliter

- Platelets ≥ 75,000 cells per microliter

- aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper
limit of normal

- Total Bilirubin < 1.5 x upper limit of normal

- Creatinine < 1.5 x upper limit of normal OR

- Creatinine Clearance ≥ 60 mL/min/1.73m2 for patients with creatinine > 1.5 x
upper limit of normal

6. The effects of mebendazole on the developing human fetus are unknown. In rats there is
evidence of a teratogenic effect, although there is no evidence of adverse effect from
women accidently taking mebendazole (at lower doses) during pregnancy. For this
reason, women of child-bearing potential should agree to use birth control while
taking mebendazole if there is a reasonable risk of pregnancy. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately.

7. Ability for patient (and if applicable parent or legal guardian) understand and the
willingness to sign a written informed consent document, or for a parent or legal
guardian to give assent for those cases where a very young patient is unable to
understand or sign the consent.

8. For the patient or parent/legal guardian to be able to comply with treatment plan,
study procedures and follow-up examinations.

9. Failed any previous front line standard of care therapy that is currently used for the
patient's initial diagnosis.

10. Ability to swallow pills, or liquid formulation and for patient or parent/legal
guardian to keep an accurate medication record.

Exclusion Criteria:

1. Patients who have known allergy to mebendazole.

2 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.

3 Patients who are taking metronidazole and cannot be safely moved to a different
antibiotic greater than 7 days prior to starting mebendazole therapy. Metronidazole and
mebendazole in combination have been associated with Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis in a case report.

4 Patients who have previously taken mebendazole as part of any experimental anti-cancer
protocol, and have failed this therapy.

5 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.

6 Pregnant women are excluded because mebendazole is a Class C agent with the potential for
teratogenic effects. Because it is not known if mebendazole is excreted in breast milk,
breastfeeding should be discontinued if the mother is treated with mebendazole.

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

8 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.

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