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