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

This is a safety (Phase 1) trial using mebendazole for recurrent pediatric brain cancers that include medulloblastoma and high grade glioma, that are no longing responding to standard therapies. The drug mebendazole is an oral drug in a chewable 500 mg orange flavored tablet. It is already approved to treat parasitic infections. The purpose of this study is to determine the safety and side effects for increasing doses of mebendazole, followed by the treatment of an additional 12 patients at the best tolerated dose.

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.