Clinical Trials /

A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

NCT01837862

Description:

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 increased progression-free and overall survival for low-grade glioma patients, particularly for those with pilomyxoid astrocytomas. High grade gliomas are more aggressive tumors with poor prognoses. The standard therapy is radiation therapy. A variety of adjuvant chemotherapeutic combinations have been used, but with disappointing results. For high-grade gliomas this study will add mebendazole to the established combination of bevacizumab and irinotecan to determine this combinations safety and efficacy

Related Conditions:
  • Anaplastic Astrocytoma
  • Brain Stem Glioma
  • Glioblastoma
  • Gliosarcoma
  • Low Grade Glioma
  • Malignant Spinal Cord Neoplasm
  • Pilomyxoid Astrocytoma
  • Pleomorphic Xanthoastrocytoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CCMC1411
  • NCT ID: NCT01837862

Conditions

  • Pilomyxoid Astrocytoma
  • Pilocytic Astrocytoma
  • Glioma, Astrocytic
  • Optic Nerve Glioma
  • Pleomorphic Xanthoastrocytoma
  • Glioblastoma Multiforme
  • Anaplastic Astrocytoma
  • Gliosarcoma
  • Diffuse Intrinsic Pontine Glioma
  • DIPG
  • Low-grade Glioma
  • Brainstem Glioma

Interventions

DrugSynonymsArms
MebendazoleVermoxLow-grade Glioma
VincristineOncovinLow-grade Glioma
CarboplatinParaplatinLow-grade Glioma
TemozolomideTemodarLow-grade Glioma
BevacizumabAvastinHigh-grade Glioma/Pontine Glioma
IrinotecanCPT-11, CamptosarHigh-grade Glioma/Pontine Glioma

Purpose

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 increased progression-free and overall survival for low-grade glioma patients, particularly for those with pilomyxoid astrocytomas. High grade gliomas are more aggressive tumors with poor prognoses. The standard therapy is radiation therapy. A variety of adjuvant chemotherapeutic combinations have been used, but with disappointing results. For high-grade gliomas this study will add mebendazole to the established combination of bevacizumab and irinotecan to determine this combinations safety and efficacy

Detailed Description

      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" design will be used for determining dose escalation.

      Phase I safety monitoring for the low-grade group will take place during a trial period
      beginning with start of therapy and ending following the tenth week of induction therapy.
      Phase I safety monitoring for the high-grade/pontine glioma group will take place during a
      trial period beginning with the start of maintenance therapy through the twelfth week of
      maintenance therapy (3 cycles).

      After determination of maximally tolerated dose for each group, the study will continue to
      evaluate efficacy of this regimen. The study will be amended for the maximally tolerated dose
      for each group to be used in the remainder of the study. Patients currently on study will
      continue with maintenance therapy. To document the degree of residual tumor, standard whole
      brain MRI with and without contrast (gadolinium) will be performed following a specified
      intervals. Following completion of therapy, patients will continue to be monitored by MRI to
      assess progression-free and overall-survival.
    

Trial Arms

NameTypeDescriptionInterventions
Low-grade GliomaExperimentalPatients on the low-grade arm will receive treatment with seven 10-week cycles of carboplatin, vincristine, temozolomide, and mebendazole.
  • Mebendazole
  • Vincristine
  • Carboplatin
  • Temozolomide
High-grade Glioma/Pontine GliomaExperimentalPatients on the high-grade glioma/pontine glioma arm will receive treatment with twelve 28-day cycles of bevacizumab, irinotecan, and mebendazole.
  • Mebendazole
  • Bevacizumab
  • Irinotecan

Eligibility Criteria

        Inclusion Criteria:

          1. Age > 1 year of age and ≤ 21 years of age

          2. Diagnosis

             2.1. Group A - Low-grade Glioma Group:

             Histology: Biopsy-proven:

               -  Pilocytic Astrocytoma

               -  Fibrillary Astrocytoma

               -  Pilomyxoid Astrocytoma

               -  Pleomorphic Xanthoastrocytoma

               -  Other low grade astrocytomas

             Children with optic pathway tumors must have evidence of progressive disease on MRI
             and/or symptoms of deteriorating vision or, progressive hypothalamic/pituitary
             dysfunction or, diencephalic syndrome or precocious puberty.

             Patients with relapsed low-grade gliomas 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 used in this study.

             2.2 Group B - High-grade Glioma/Pontine Glioma Group:

             Histology: Biopsy-proven

               -  Anaplastic astrocytoma

               -  Glioblastoma multiforme

               -  Gliosarcoma.

             Patients with primary spinal cord malignant gliomas are eligible.

             For primary brainstem tumors, histologic verification is not required. Patients are
             eligible when diagnosed with clinical and radiographic (MRI) evidence of tumors which
             diffusely involve the brainstem. Patients with tumors which intrinsically (greater
             than 50% intra-axial) involve the pons or pons and medulla or pons and midbrain or
             entire brainstem are eligible. Tumors may contiguously involve the thalamus or upper
             cervical cord.

          3. Timing of therapy:

             Patients must be enrolled before treatment begins. Treatment must start within 14 days
             of study enrollment.

             All clinical and laboratory studies to determine eligibility must be performed within
             7 days prior to enrollment unless otherwise indicated in the eligibility section.

          4. Adequate hematologic, renal, liver function as demonstrated by laboratory values.

          5. Negative pregnancy test in women of childbearing potential within 7 days of initiating
             investigational therapy

          6. Life expectancy ≥ 3 months

          7. Concurrent medications: It is recommended that patients are weaned off or are on a
             tapering dose of corticosteroids before starting therapy on study.

          8. Patient or legal guardian must give written, informed consent or assent (when
             applicable)

          9. Recent mothers must agree not to breast feed while receiving medications on study.

        Exclusion criteria:

          1. Age < 1 year or > 21 years

          2. Patients who have known allergy to mebendazole or benzimidazole class drugs.

          3. 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 .

          4. Patients who are taking metronidazole and cannot be safely moved to a different
             antibiotic greater than 7 days prior to starting mebendazole therapy.

          5. Pregnant female patients are not eligible for this study. Pregnancy tests with a
             negative result must be obtained in all post-menarchal females.

          6. Lactating females must agree they will not breastfeed a child while on this study.

          7. Males and females of reproductive potential may not participate unless they agree to
             use an effective contraceptive method and continue to do so for at least 6 months
             after the completion of therapy.

          8. Patients who are unable to take oral medications because of significant vomiting will
             be excluded.

          9. Group A - Low-grade Glioma Group ONLY:

             Patients who have failed prior chemotherapy with vincristine, carboplatin, or
             temozolomide for this tumor are excluded.

             Patients with Neurofibromatosis Type 1

         10. Group B - High-grade Glioma/Pontine Glioma Group ONLY:

        Patients who failed prior chemotherapy with bevacizumab or irinotecan for this tumor are
        excluded.

        Patients who progressed on or within 12 weeks after completion of radiotherapy are
        excluded.

        Patients with a history or current condition that would preclude the use of bevacizumab
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximally tolerated dose of mebendazole in combination with vincristine, carboplatin, and temozolomide
Time Frame:Assessed after the 10 week Induction cycle
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Survival of patients with low-grade gliomas
Time Frame:3-years post-treatment
Safety Issue:
Description: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.
Measure:Survival of patients with high-grade gliomas
Time Frame:3-years post-treatment
Safety Issue:
Description: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.
Measure:Frequency of cerebrospinal fluid (CSF) dissemination in pilomyxoid astrocytoma
Time Frame:3 years post-treatment
Safety Issue:
Description:The frequency of tumor dissemination in the CSF of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole.
Measure:Partial or complete response rate on MRI of patients with high-grade gliomas/pontine gliomas
Time Frame:3-years post-treatment
Safety Issue:
Description: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.
Measure:Partial or complete response rate on MRI of patients with low-grade gliomas
Time Frame:3-years post-treatment
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Julie Krystal

Trial Keywords

  • pilomyxoid astrocytoma
  • Pilocytic Astrocytoma
  • Glioma
  • Optic Nerve Glioma
  • mebendazole
  • Pleomorphic Xanthoastrocytoma
  • glioblastoma multiforme
  • anaplastic astrocytoma
  • gliosarcoma
  • diffuse intrinsic pontine glioma
  • DIPG
  • low-grade glioma
  • high-grade glioma
  • brainstem glioma
  • pediatric

Last Updated

March 22, 2019