Clinical Trial: A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

Brief Summary:

This is a study to determine the safety and efficacy of the drug, mebendazole, when used in combination with standard chemotherapy drugs for the treatment of pediatric brain tumors. Mebendazole is a drug used to treat infections with intestinal parasites and has a long track record of safety in humans. Recently, it was discovered that mebendazole may be effective in treating cancer as well, in particular brain tumors. Studies using both cell cultures and mouse models demonstrated that mebendazole was effective in decreasing the growth of brain tumor cells.

This study focuses on the treatment of a category of brain tumors called gliomas. Low-grade gliomas are tumors arising from the glial cells of the central nervous system and are characterized by slower, less aggressive growth than that of high-grade gliomas. Some low-grade gliomas have a more aggressive biology and an increased likelihood of resistance or recurrence.

Low-grade gliomas are often able to be treated by observation alone if they receive a total surgical resection. However, tumors which are only partially resected and continue to grow or cause symptoms, or those which recur following total resection require additional treatment, such as chemotherapy. Due to their more aggressive nature, pilomyxoid astrocytomas, even when totally resected, will often be treated with chemotherapy. The current first-line treatment at our institution for these low-grade gliomas involves a three-drug chemotherapy regimen of vincristine, carboplatin, and temozolomide. However, based on our data from our own historical controls, over 50% of patients with pilomyxoid astrocytomas will continue to have disease progression while on this treatment. We believe that mebendazole in combination with vincristine, carboplatin, and temozolomide may provide an additional therapeutic benefit with

Detailed Summary:

This is a phase I/II study of mebendazole in combination with standard of care agents for pediatric patients with gliomas. Patients with low-grade gliomas will receive a regimen of mebendazole in combination with vincristine, carboplatin, and temozolomide. Patients with high-grade gliomas and diffuse intrinsic pontine gliomas will receive a regimen of mebendazole in combination with bevacizumab and irinotecan. Surgical resection of the tumor will be attempted initially with the goal of achieving a gross total resection without substantial neurologic deficit. Subtotal resection may be preferable depending on the location of the tumor. Optic pathway gliomas and diffuse intrinsic pontine gliomas may remain unresected. Patients with high-grade gliomas or diffuse intrinsic pontine gliomas will undergo local irradiation of their tumor before beginning protocol treatment. Low-grade glioma patients will not receive radiation therapy. Patients who have been previously treated with chemotherapy will be eligible for the study provided they have not previously failed therapy with any of the chemotherapeutic agents.

Patients with eligible tumors will be consented for enrollment into the study. The study patients will be divided into two groups (low-grade glioma and high-grade/pontine glioma) for the purpose of determining the maximally tolerated dose of mebendazole. These two groups will be treated independently with regard to patient accrual, dose escalation, and evaluation of toxicity. In addition to their standard chemotherapy regimen, patients in both cohorts will receive mebendazole. Mebendazole doses will be escalated from the initial dose level of 50 mg/kg/day divided twice daily, to a second dose level of 100 mg/kg/day divided twice daily, to the final dose level of 200 mg/kg/day divided twice daily, in cohorts of three patients per dose level. A standard "3+3" desig
Sponsor: Mark Atlas

Current Primary Outcome:

• Maximally tolerated dose of mebendazole in combination with vincristine, carboplatin, and temozolomide [ Time Frame: Assessed after the 10 week Induction cycle ]
  Low-grade glioma patients will receive an assigned dose of mebendazole twice daily in combination with vincristine, carboplatin and temozolomide. During a 10 week induction period, patients will be assessed for dose-limiting toxicity that is beyond the expected toxicity from the standard regimen of vincristine, carboplatin, and temozolomide alone. This outcome measure will use a standard 3+3 design to dose-escalate mebendazole in three dose cohorts of 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day.
• Maximally tolerated dose of mebendazole in combination with bevacizumab and irinotecan. [ Time Frame: Assessed after the first 3 maintenance cycles (12 weeks) ]
  High-grade glioma/pontine glioma patients will receive an assigned dose of mebendazole twice daily in combination with bevacizumab and irinotecan. During the first three maintenance therapy cycles (12 weeks), patients will be assessed for dose-limiting toxicity that is beyond the expected toxicity from the standard regimen of bevacizumab and irinotecan alone. This outcome measure will use a standard 3+3 design to dose-escalate mebendazole in three dose cohorts of 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day.

Original Primary Outcome:

• Maximally tolerated dose of mebendazole in combination with vincristine, carboplatin, and temozolomide [ Time Frame: Assessed during the 10 week Induction cycle for each patient ]
  Patients enrolled on the phase I portion of the study will receive a standard dose of 100 mg of mebendazole twice daily in combination with vincristine, carboplatin and temozolomide. During a 10 week induction period, patients will be assessed for "adverse events" defined as grade III-IV non-hematologic toxicity that is beyond the expected toxicity from the standard regimen of vincristine, carboplatin, and temozolomide alone. If one or fewer of the patients experiences an adverse event during the 10 week trial period, then mebendazole 100 mg twice daily will be considered the maximally tolerated dose.
• Survival of patients with pilomyxoid astrocytoma [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.

Current Secondary Outcome:

• Survival of patients with low-grade gliomas [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with low-grade gliomas treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.
• Survival of patients with high-grade gliomas [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with high-grade gliomas treated with bevacizumab, irinotecan, and mebendazole in combination following surgical resection to the extent feasible and local irradiation.
• Frequency of cerebrospinal fluid (CSF) dissemination in pilomyxoid astrocytoma [ Time Frame: 3 years post-treatment ]
  The frequency of tumor dissemination in the CSF of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole.
• Partial or complete response rate on MRI of patients with high-grade gliomas/pontine gliomas [ Time Frame: 3-years post-treatment ]
  The percentage of patients demonstrating a partial (greater than 50% decrease in tumor volume in 3 dimensions) or complete response on MRI in patients with high-grade gliomas treated with mebendazole in combination with bevacizumab and irinotecan, after surgical resection, to the extent feasible and local irradiation.
• Partial or complete response rate on MRI of patients with low-grade gliomas [ Time Frame: 3-years post-treatment ]
  The percentage of patients demonstrating a partial (greater than 50% decrease in tumor volume in 3 dimensions) or complete response on MRI in patients with low-grade gliomas treated with mebendazole in combination with vincristine, carboplatin and temozolomide after surgical resection, to the extent feasible.

Original Secondary Outcome:

• Survival of patients with juvenile pilocytic astrocytomas [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with recurrent or progressive juvenile pilocytic astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.
• Survival of patients with optic pathway gliomas [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with symptomatic or progressive optic pathway gliomas (OPG) treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.
• Frequency of cerebrospinal fluid (CSF) dissemination in pilomyxoid astrocytoma [ Time Frame: 3 years post-treatment ]
  The frequency of tumor dissemination in the CSF of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole.
• Survival of patients with pleomorphic xanthoastrocytomas [ Time Frame: 3-years post-treatment ]
  3-year event-free survival (EFS) and overall survival (OS) of patients with pleomorphic xanthoastrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.

Dates:
Date Received: April 16, 2013
Date Started: April 2015
Date Completion: April 2020
Last Updated: January 30, 2017
Last Verified: January 2017