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

• ClinicalTrials.gov Identifier: NCT01837862
• Recruitment Status: Recruiting
• First Posted: April 23, 2013
• Last Update Posted: April 13, 2023
• Sponsor: Julie Krystal
• Collaborator: Janssen Pharmaceuticals
• Information provided by (Responsible Party): Julie Krystal, Northwell Health

Tracking Information

• First Submitted Date: April 16, 2013
• First Posted Date: April 23, 2013
• Last Update Posted Date: April 13, 2023
• Actual Study Start Date: October 22, 2013
• Estimated Primary Completion Date: April 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2015)

• 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 Measures (submitted: April 18, 2013)

• 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 Measures (submitted: December 15, 2014)

• 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 Measures (submitted: April 18, 2013)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• Drug: Mebendazole
  Mebendazole will be given orally twice daily for over the course of treatment (70 weeks for low-grade glioma patients, 48 weeks for high-grade glioma/pontine glioma patients). Mebendazole will be prescribed according to the particular dose cohort for each patient (50 mg/kg/day, 100 mg/kg/day, or 200 mg/kg/day).
  Other Name: Vermox
• Drug: Vincristine
  Low-grade glioma patients only. 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 intravenously 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
  Low-grade glioma patients only. Carboplatin will be dosed at 175 mg/m2. Carboplatin will be administered intravenously 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
  Low-grade glioma patients only. Temozolomide will be dosed at 200 mg/m2/day. Temozolomide will be given orally 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
• Drug: Bevacizumab
  High-grade glioma/pontine glioma patients only. Bevacizumab will be dosed at 10mg/kg/dose. Bevacizumab will be administered intravenously on Days 1 and 15 of each maintenance cycle.
  Other Name: Avastin
• Drug: Irinotecan
  High-grade glioma/pontine glioma patients only. Irinotecan will be administered at doses 125 mg/m2, 150 mg/m2, 250 mg/m2, or 300 mg/m2, depending on patient tolerance and concomitant enzyme-inducing anti-epileptic medication use. Irinotecan will be administered intravenously on Days 1 and 15 of each maintenance cycle.
  Other Names:

  • CPT-11
  • Camptosar

Study Arms

• Experimental: Low-grade Glioma
  Patients on the low-grade arm will receive treatment with seven 10-week cycles of carboplatin, vincristine, temozolomide, and mebendazole.
  Interventions:

  • Drug: Mebendazole
  • Drug: Vincristine
  • Drug: Carboplatin
  • Drug: Temozolomide
• Experimental: High-grade Glioma/Pontine Glioma

  Patients on the high-grade glioma/pontine glioma arm will receive treatment with twelve 28-day cycles of bevacizumab, irinotecan, and mebendazole.

  *High grade arm enrollment complete, no additional spots

  Interventions:

  • Drug: Mebendazole
  • Drug: Bevacizumab
  • Drug: Irinotecan

Publications *

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Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 15, 2014): 36
• Original Estimated Enrollment (submitted: April 18, 2013): 20
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: April 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Julie Krystal, MD; 718-470-3460; Jkrystal12@northwell.edu

Contact: Derek R Hanson, MD; 551-996-5437; DHanson@hackensackumc.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01837862
• Other Study ID Numbers: CCMC1411
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Julie Krystal, Northwell Health
• Original Responsible Party: Mark Atlas, Northwell Health, Chair, Childhood Brain and Spinal Cord Tumor Program
• Current Study Sponsor: Julie Krystal
• Original Study Sponsor: Mark Atlas
• Collaborators: Janssen Pharmaceuticals

Investigators

• Principal Investigator: Julie Krystal, MD; Northwell Health

• PRS Account: Northwell Health
• Verification Date: April 2023