Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT02644291 |
|
Recruitment Status :
Completed
First Posted : December 31, 2015
Last Update Posted : June 23, 2022
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Medulloblastoma Astrocytoma, Grade III Glioblastoma Anaplastic Astrocytoma Brain Stem Neoplasms, Malignant Oligodendroblastoma Anaplastic Oligodendroglioma Malignant Glioma | Drug: Mebendazole | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 16 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors |
| Study Start Date : | May 2016 |
| Actual Primary Completion Date : | June 9, 2022 |
| Actual Study Completion Date : | June 9, 2022 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: mebendazole
oral mebendazole as dose escalation (three groups), or l oral mebendazole at maximum dose for extended cohort. Given in 3 divided doses with meals as chewable 500 mg tablets based on calculated patient surface area.
|
Drug: Mebendazole
chewable mebendazole tablets that can also be crushed and mixed with food or drink to be taken daily with meals
Other Names:
|
- Adverse events attributed to mebendazole for patients enrolled in this study [ Time Frame: duration of study, approximately two years ]cumulative adverse events from mebendazole therapy in pediatric brain cancer patients
- Overall survival for patients enrolled in this study [ Time Frame: duration of study , approximately two years ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 1 Year to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients must have a confirmed recurrent/progressive brain malignancy that have failed at least one prior treatment regimen.
- 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.
- Karnofsky Performance Score (KPS) > 50% for patients ≥10 years of age. Lansky score of ≥ 50 for children < 10 years of age.
- Life expectancy greater than 10 weeks.
-
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
- 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.
- 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.
- For the patient or parent/legal guardian to be able to comply with treatment plan, study procedures and follow-up examinations.
- Failed any previous front line standard of care therapy that is currently used for the patient's initial diagnosis.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02644291
| United States, Florida | |
| Johns Hopkins All Children's Hospital | |
| Saint Petersburg, Florida, United States, 33701 | |
| United States, Maryland | |
| Johns Hopkins University School of Medicine | |
| Baltimore, Maryland, United States, 21231 | |
| Principal Investigator: | Kenneth J Cohen, MD | Johns Hopkins University |
| Responsible Party: | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
| ClinicalTrials.gov Identifier: | NCT02644291 |
| Other Study ID Numbers: |
J15211 IRB00072999 ( Other Identifier: JHMIRB ) |
| First Posted: | December 31, 2015 Key Record Dates |
| Last Update Posted: | June 23, 2022 |
| Last Verified: | September 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Plan Description: | A peer reviewed publication in a medical journal with the results from the study is planned upon completion of the study,that may/may not have data from individual participants compliant with HIPPA protection. |
|
medulloblastoma Diffuse Intrinsic Pontine Glioma (DIPG) high grade glioma glioblastoma brain stem malignant glioma |
|
Glioblastoma Glioma Astrocytoma Medulloblastoma Oligodendroglioma Neoplasms Brain Stem Neoplasms Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Brain Neoplasms Central Nervous System Neoplasms |
Nervous System Neoplasms Neoplasms by Site Brain Diseases Central Nervous System Diseases Nervous System Diseases Neuroectodermal Tumors, Primitive Infratentorial Neoplasms Mebendazole Piperazine Piperazine citrate DMP 777 Antinematodal Agents Anthelmintics Antiparasitic Agents Anti-Infective Agents |