Phase I study of Mebendazole in Newly Diagnosed High-Grade gliomas
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. MBZ is approved by the Food and Drug Administration (FDA) and commonly used in the treatment of worm infections. MBZ is not approved for the treatment of brain tumors and therefore its use in this study is investigational. However, the FDA is allowing the use of MBZ in this study. It is standard to treat people with newly diagnosed malignant gliomas using temozolomide alone following surgery and then radiation in combination with temozolomide. Temozolomide is a chemotherapy drug that is approved by the FDA for treating brain tumors. If you agree to be a part of this study, you will be given mebendazole in addition to temozolomide. This is the first time that the combination of temozolomide and mebendazole has been given to people. Thus, the effects of the drug, good and bad, and the correct dose of the drug to give are unknown.
Inclusion Criteria: 1.Patients must have histologically confirmed newly diagnosed high-grade glioma (WHO Grade III or IV) 2.ï¿½ 18 years of age. 3.Karnofsky Performance Score ï¿½ 60% 4.Life expectancy greater than 12 weeks 5.Patients must have adequate organ and marrow function as defined below: ï¿½Leukocytes ï¿½ 3,000/mcL ï¿½Absolute Neutrophil Count ï¿½ 1,500/mcL ï¿½Platelets ï¿½ 100,000/mcL ï¿½AST/ALTï¿½ 2.5 x upper limit of normal ï¿½Total Bilirubin less than 1.5 x upper limit of normal ï¿½Creatinine less than 1.5 x upper limit of normal OR ï¿½Creatinine Clearanceï¿½ 60 mL/min/1.73m2 for patients with creatinine greater than 1.5 x upper limit of normal 6.Participants of childbearing age must use effective contraception. 7.Ability and the willingness to sign a written informed consent document 8.Be able to comply with treatment plan, study preocedures and follow-up examinations 9.Completed greater than 80% of the prescribed radiation therapy and concurrent temozolomide according to the Stupp regimen without grade 3 or 4 hematologic toxicity 10.Patients may have received Gliadel during surgery 11.Ability to swallow pills and keep medication record 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, carbamazapine, 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 because mebendazole is a Class C agent with the potential for teratogenic effects. Because it is not know if mebendazole is excreted in breast milk, breastfeeding should be discontinued if the mother is treated with mebendazole. 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.
All patients must have histological confirmation of a high-grade glioma (WHO Grade III or IV) by either biopsy or resection. Following the 4 week break after combined temozolomide and radiation therapy, participants will receive daily oral mebendazole concurrent with the standard chemotherapy (temozolomide) regimen as described in the Stupp protocol. There will be no limit on the number of cycles of mebendazole treatment; however, all patients who experience progressive disease or intolerable adverse effects will discontinue mebendazole treatment. There will be an expanded cohort at the highest tolerated dose of mebendazole. The treating oncologist will determine whether to stop TMZ after 6 cycles.
05/20/2013 04:02 AM