Pilot Study of Mebendazole to Treat Pediatric Low-Grade Gliomas

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2013 by North Shore Long Island Jewish Health System
Sponsor:
Information provided by (Responsible Party):
Mark Atlas, North Shore Long Island Jewish Health System
ClinicalTrials.gov Identifier:
NCT01837862
First received: April 16, 2013
Last updated: April 22, 2013
Last verified: April 2013
  Purpose

This is a study to determine the safety and efficacy of the drug, mebendazole, when used in combination with three additional chemotherapy agents, vincristine, carboplatin, and temozolomide, 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 low-grade 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. The category of low-grade glioma includes many subtypes. One such subtype, pilomyxoid astrocytoma, is a grade II tumor which has an aggressive nature with an increased rate of recurrence and decreased survival rate compared to other low-grade gliomas.

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.


Condition Intervention Phase
Pilomyxoid Astrocytoma
Pilocytic Astrocytoma
Glioma, Astrocytic
Optic Nerve Glioma
Pleomorphic Xanthoastrocytoma
Drug: Mebendazole
Drug: Vincristine
Drug: Carboplatin
Drug: Temozolomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I and II Pilot Study of Mebendazole in Combination With Vincristine, Carboplatin, and Temozolomide in Children With Low-Grade Gliomas

Resource links provided by NLM:


Further study details as provided by North Shore Long Island Jewish Health System:

Primary Outcome Measures:
  • Maximally tolerated dose of Mebendazole in combination with Vincristine, Carboplatin, and Temozolomide [ Time Frame: Assessed during the 10 week Induction cycle for each patient ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Survival of patients with juvenile pilocytic astrocytomas [ Time Frame: 3-years post-treatment ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 20
Study Start Date: June 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Control
Patients on the control arm will receive seven 10-week cycles will consisting of carboplatin, vincristine, and temozolomide.
Drug: Vincristine
Vincristine will be dosed as per the following: For patients < 12kg: 0.05 mg/kg; for patient > 12kg: 1.5mg/m2 (maximal dose 2.0 mg). Vincristine will be administered on Day 1 of weeks 0,1,2,3,4,5 during the 10-week induction cycle and on Day 1 of Weeks 0,1,2 of the six 10-week maintenance cycles.
Other Name: oncovin
Drug: Carboplatin
Carboplatin will be dosed at 175 mg/m2. Carboplatin will be administered on Day 1 of Weeks 0,1,2,3 of the 10-week Induction cycle, and on Day 1 of Weeks 0,1,2,3 during the six 10-week maintenance cycles.
Other Name: Paraplatin
Drug: Temozolomide
Temozolomide will be dosed at 200 mg/m2/day. Temozolomide will be given for 5 days during Week 6 of the 10-week induction cycle and for 5 days during Week 6 of the six 10-week maintenance cycles.
Other Name: Temodar
Experimental: Mebendazole
Patients on the Mebendazole arm will receive seven 10-week cycles of carboplatin, vincristine, temozolomide, and mebendazole.
Drug: Mebendazole
Mebendazole will be given at a dose of 100mg orally twice daily for 70 weeks over the course of treatment.
Drug: Vincristine
Vincristine will be dosed as per the following: For patients < 12kg: 0.05 mg/kg; for patient > 12kg: 1.5mg/m2 (maximal dose 2.0 mg). Vincristine will be administered on Day 1 of weeks 0,1,2,3,4,5 during the 10-week induction cycle and on Day 1 of Weeks 0,1,2 of the six 10-week maintenance cycles.
Other Name: oncovin
Drug: Carboplatin
Carboplatin will be dosed at 175 mg/m2. Carboplatin will be administered on Day 1 of Weeks 0,1,2,3 of the 10-week Induction cycle, and on Day 1 of Weeks 0,1,2,3 during the six 10-week maintenance cycles.
Other Name: Paraplatin
Drug: Temozolomide
Temozolomide will be dosed at 200 mg/m2/day. Temozolomide will be given for 5 days during Week 6 of the 10-week induction cycle and for 5 days during Week 6 of the six 10-week maintenance cycles.
Other Name: Temodar

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≤ 21 years
  2. Timing of therapy

    1. Patients must be enrolled before treatment begins. Treatment must start within 14 days of study enrollment.
    2. Patients with pilomyxoid astrocytomas and pleomorphic xanthoastrocytoma must be newly diagnosed and start therapy within 28 days of diagnostic biopsy.
    3. Patients pilocytic astrocytomas and optic pathway gliomas who are observed and later noted to have:

      • progression on imaging studies, or
      • progression of symptoms, or
      • appearance of new symptoms are eligible, provided that the patients have previous diagnostic biopsy of pilocytic astrocytoma or optic pathway glioma, or MRI consistent with optic pathway glioma. These patients do not need another biopsy at the time of progression and therapy should start within 4 weeks after progression. These patients must have a baseline MRI of the primary lesion not more than 30 days prior to initiation of therapy.
  3. Histological diagnosis:

    1. Pilomyxoid Astrocytomas
    2. Pleomorphic Xanthoastrocytomas, without anaplastic transformation
    3. Pilocytic Astrocytomas
    4. Optic Pathway Gliomas

      • Patients with optic pathway gliomas are eligible without biopsy, but must have MRI consistent with OPG.
  4. Adequate hematologic, renal, liver function as demonstrated by laboratory values performed within 21 days, inclusive prior to administration to temozolomide:

    1. Absolute neutrophil count ≥ 1,000/ul
    2. Hemoglobin ≥8.0 gm/dl
    3. Platelet count ≥ 100,000/ul
    4. Adequate Liver Function Defined As

      • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
      • Alanine Aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) for age.
    5. Adequate Renal Function Defined As

      • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70ml/min/1.73m2
      • A normal serum creatinine based on age and gender
  5. Life expectancy ≥ 3 months
  6. Concurrent medications: It is recommended that patients are weaned off or are on a tapering dose of corticosteroids before starting therapy on study.
  7. Patient or legal guardian must give written, informed consent or assent (when applicable)
  8. Recent mothers must agree not to breast feed while receiving medications on study. All females of childbearing age must have a negative pregnancy test within two weeks of beginning study therapy.

Exclusion Criteria:

  1. Patients who received prior chemotherapy or radiotherapy for this tumor are excluded.
  2. Pregnant and Nursing Women are excluded as temozolomide is potentially mutagenic.
  3. Men &Women who are sexually active and refuse birth control are excluded from participating in this study
  4. Patients who are unable to take oral medications because of significant vomiting will be excluded.
  5. Patients with Neurofibromatosis Type 1
  6. Patients who have known allergy to mebendazole or benzimidazole class drugs.
  7. 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 .
  8. Patients who are taking metronidazole and cannot be safely moved to a different antibiotic greater than 7 days prior to starting mebendazole therapy.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01837862

Contacts
Contact: Mark P Atlas, MD 718-470-3460 matlas@nshs.edu
Contact: Derek R Hanson, MD 718-470-3460 dhanson3@nshs.edu

Locations
United States, New York
Cohen Children's Medical Center of New York Not yet recruiting
New Hyde Park, New York, United States, 11040
Contact: Mark P Atlas, MD    718-470-3460    matlas@nshs.edu   
Contact: Derek R Hanson, MD    7184703460    dhanson3@nshs.edu   
Principal Investigator: Mark P Atlas, MD         
Sub-Investigator: Derek R Hanson, MD         
Sub-Investigator: Arlene Redner, MD         
Sub-Investigator: Alyssa Quinlan, PA         
Sponsors and Collaborators
Mark Atlas
Investigators
Principal Investigator: Mark P Atlas, MD North Shore-LIJ
  More Information

Publications:

Responsible Party: Mark Atlas, Director, Childhood Brain and Spinal Cord Tumor Program, Investigator, North Shore Long Island Jewish Health System
ClinicalTrials.gov Identifier: NCT01837862     History of Changes
Other Study ID Numbers: CCMC1311
Study First Received: April 16, 2013
Last Updated: April 22, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by North Shore Long Island Jewish Health System:
pilomyxoid astrocytoma
Pilocytic Astrocytoma
Glioma
Optic Nerve Glioma
mebendazole
Pleomorphic Xanthoastrocytoma

Additional relevant MeSH terms:
Glioma
Optic Nerve Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Optic Nerve Neoplasms
Cranial Nerve Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Peripheral Nervous System Neoplasms
Cranial Nerve Diseases
Nervous System Diseases
Optic Nerve Diseases
Eye Diseases
Temozolomide
Carboplatin
Dacarbazine
Vincristine
Mebendazole
Piperazine
Piperazine citrate
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on September 16, 2014