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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT01837862
Other study ID # CCMC1411
Secondary ID
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date October 22, 2013
Est. completion date April 2025

Study information

Verified date April 2023
Source Northwell Health
Contact Julie Krystal, MD
Phone 718-470-3460
Email Jkrystal12@northwell.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 36
Est. completion date April 2025
Est. primary completion date April 2024
Accepts healthy volunteers No
Gender All
Age group 1 Year to 21 Years
Eligibility 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

Study Design


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).
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.
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.
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.
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.
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.

Locations

Country Name City State
United States Cohen Children's Medical Center of New York New Hyde Park New York

Sponsors (2)

Lead Sponsor Collaborator
Julie Krystal Janssen Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (42)

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Fisher BJ, Leighton CC, Vujovic O, Macdonald DR, Stitt L. Results of a policy of surveillance alone after surgical management of pediatric low grade gliomas. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):704-10. doi: 10.1016/s0360-3016(01)01705-9. — View Citation

Friedman HS, Krischer JP, Burger P, Oakes WJ, Hockenberger B, Weiner MD, Falletta JM, Norris D, Ragab AH, Mahoney DH Jr, et al. Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study. J Clin Oncol. 1992 Feb;10(2):249-56. doi: 10.1200/JCO.1992.10.2.249. — View Citation

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Giannini C, Scheithauer BW, Burger PC, Brat DJ, Wollan PC, Lach B, O'Neill BP. Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer. 1999 May 1;85(9):2033-45. — View Citation

Gil-Grande LA, Boixeda D, Garcia-Hoz F, Barcena R, Lledo A, Suarez E, Pascasio JM, Moreira V. Treatment of liver hydatid disease with mebendazole: a prospective study of thirteen cases. Am J Gastroenterol. 1983 Sep;78(9):584-8. — View Citation

Janss AJ, Grundy R, Cnaan A, Savino PJ, Packer RJ, Zackai EH, Goldwein JW, Sutton LN, Radcliffe J, Molloy PT, et al. Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. Cancer. 1995 Feb 15;75(4):1051-9. doi: 10.1002/1097-0142(19950215)75:43.0.co;2-s. — View Citation

Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer. 1979 Nov;44(5):1839-52. doi: 10.1002/1097-0142(197911)44:53.0.co;2-0. — View Citation

Komotar RJ, Carson BS, Rao C, Chaffee S, Goldthwaite PT, Tihan T. Pilomyxoid astrocytoma of the spinal cord: report of three cases. Neurosurgery. 2005;56(1):191. doi: 10.1227/01.NEU.0000146212.95421.B3. — View Citation

Komotar RJ, Mocco J, Jones JE, Zacharia BE, Tihan T, Feldstein NA, Anderson RC. Pilomyxoid astrocytoma: diagnosis, prognosis, and management. Neurosurg Focus. 2005 Jun 15;18(6A):E7. — View Citation

Lefkowitz IB, Packer RJ, Sutton LN, Siegel KR, Bruce DA, Evans AE, Schut L. Results of the treatment of children with recurrent gliomas with lomustine and vincristine. Cancer. 1988 Mar 1;61(5):896-902. doi: 10.1002/1097-0142(19880301)61:53.0.co;2-c. — View Citation

Mamelak AN, Prados MD, Obana WG, Cogen PH, Edwards MS. Treatment options and prognosis for multicentric juvenile pilocytic astrocytoma. J Neurosurg. 1994 Jul;81(1):24-30. doi: 10.3171/jns.1994.81.1.0024. — View Citation

Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA. Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2002 Sep;8(9):2963-9. — View Citation

Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. doi: 10.1002/cncr.22961. — View Citation

Opocher E, Kremer LC, Da Dalt L, van de Wetering MD, Viscardi E, Caron HN, Perilongo G. Prognostic factors for progression of childhood optic pathway glioma: a systematic review. Eur J Cancer. 2006 Aug;42(12):1807-16. doi: 10.1016/j.ejca.2006.02.022. Epub 2006 Jun 30. — View Citation

Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, Jakacki R, Kurczynski E, Needle M, Finlay J, Reaman G, Boyett JM. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997 May;86(5):747-54. doi: 10.3171/jns.1997.86.5.0747. — View Citation

Packer RJ, Sutton LN, Bilaniuk LT, Radcliffe J, Rosenstock JG, Siegel KR, Bunin GR, Savino PJ, Bruce DA, Schut L. Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: an update. Ann Neurol. 1988 Jan;23(1):79-85. doi: 10.1002/ana.410230113. — View Citation

Paraskevopoulos D, Patsalas I, Karkavelas G, Foroglou N, Magras I, Selviaridis P. Pilomyxoid astrocytoma of the cervical spinal cord in a child with rapid progression into glioblastoma: case report and literature review. Childs Nerv Syst. 2011 Feb;27(2):313-21. doi: 10.1007/s00381-010-1171-5. Epub 2010 May 12. — View Citation

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Sasaki J, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay T. The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. Mol Cancer Ther. 2002 Nov;1(13):1201-9. — View Citation

Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009 Nov;24(11):1397-408. doi: 10.1177/0883073809342005. — View Citation

Silva MM, Goldman S, Keating G, Marymont MA, Kalapurakal J, Tomita T. Optic pathway hypothalamic gliomas in children under three years of age: the role of chemotherapy. Pediatr Neurosurg. 2000 Sep;33(3):151-8. doi: 10.1159/000028996. — View Citation

Tihan T, Fisher PG, Kepner JL, Godfraind C, McComb RD, Goldthwaite PT, Burger PC. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol. 1999 Oct;58(10):1061-8. doi: 10.1097/00005072-199910000-00004. — View Citation

Tsugu H, Oshiro S, Yanai F, Komatsu F, Abe H, Fukushima T, Nomura Y, Matsumoto S, Nabeshima K, Takano K, Utsunomiya H. Management of pilomyxoid astrocytomas: our experience. Anticancer Res. 2009 Mar;29(3):919-26. — View Citation

Vutova K, Mechkov G, Vachkov P, Petkov R, Georgiev P, Handjiev S, Ivanov A, Todorov T. Effect of mebendazole on human cystic echinococcosis: the role of dosage and treatment duration. Ann Trop Med Parasitol. 1999 Jun;93(4):357-65. doi: 10.1080/00034989958357. — View Citation

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* Note: There are 42 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Maximally tolerated dose of mebendazole in combination with vincristine, carboplatin, and temozolomide 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. Assessed after the 10 week Induction cycle
Primary Maximally tolerated dose of mebendazole in combination with bevacizumab and irinotecan. 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. Assessed after the first 3 maintenance cycles (12 weeks)
Secondary Survival of patients with low-grade gliomas 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. 3-years post-treatment
Secondary Survival of patients with high-grade gliomas 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. 3-years post-treatment
Secondary Frequency of cerebrospinal fluid (CSF) dissemination in pilomyxoid astrocytoma The frequency of tumor dissemination in the CSF of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole. 3 years post-treatment
Secondary Partial or complete response rate on MRI of patients with high-grade gliomas/pontine gliomas 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. 3-years post-treatment
Secondary Partial or complete response rate on MRI of patients with low-grade gliomas 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. 3-years post-treatment
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