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A Phase I and II Pilot Study of Mebendazole in Combination With Vincristine, Carboplatin, and Temozolomide in Children With Low-Grade Gliomas

Phase 1/Phase 2
21 Years
Not Enrolling
Pilomyxoid Astrocytoma, Pilocytic Astrocytoma, Glioma, Astrocytic, Optic Nerve Glioma, Pleomorphic Xanthoastrocytoma

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Trial Information

A Phase I and II Pilot Study of Mebendazole in Combination With Vincristine, Carboplatin, and Temozolomide in Children With Low-Grade Gliomas

Pilomyxoid astrocytoma is a variant subtype of pilocytic astrocytoma, which follows a more
variable and aggressive course than that of pilocytic astrocytomas with decreased duration
of disease-free and overall survival. There is no current standard of care in treating
patients with pilomyxoid astrocytoma. Surgery is often the primary treatment strategy if the
tumor is amenable to resection. However, gross total resection is often not possible due to
the common locations of these lesions and the severe morbidity associated with aggressive
resection. The long-term biological behavior of residual tumor often necessitates the use of
adjuvant chemotherapy to improve disease progression and recurrence rates. To date, there
are no published clinical trials focused specifically on the treatment of pilomyxoid

In 2002, a Children's Oncology Group phase II pilot study was initiated to evaluate the
combination of carboplatin, vincristine, and temozolomide in children with progressive or
symptomatic low-grade gliomas. The full data from this study has yet to be released and the
latest reports do not give outcome results specific to the group of patients with pilomyxoid
astrocytomas. This regimen is the current first-line treatment used at our institution for
children with pilomyxoid astrocytoma. However, based on our own historical patient data,
over 50% of patients with pilomyxoid astrocytoma will continue to progress while on this

Mebendazole is a benzimidazole drug developed for the treatment of human parasitic
infections. Recently, mebendazole has displayed efficacy in numerous cancer models including
glioblastoma multiforme, an aggressive high-grade form of glioma. A mouse glioblastoma model
demonstrated that mebendazole significantly inhibited tumor growth and extended mean
survival by 63% compared to controls. The combination of mebendazole and temozolomide
displayed a similar anti-tumor effect, prolonging survival by 72% over controls. The
pre-clinical efficacy of mebendazole in glioblastoma multiforme, its ability to cross the
blood brain barrier, and its track record of safety make mebendazole a strong candidate for
the treatment of low-grade glioma.

This is a phase I-II pilot study of mebendazole in combination with our current regimen of
carboplatin, vincristine, and temozolomide for treatment of pediatric patients with
pilomyxoid astrocytoma, and other progressive or symptomatic low-grade gliomas. We believe
that mebendazole in combination with our current regimen may provide an additional
therapeutic benefit for low-grade glioma patients, particularly those with pilomyxoid

This pilot study includes both phase I and II portions. The objective of the phase I
portion is to determine if the standard dose of mebendazole 100 mg twice daily is
"well-tolerated" when used in combination with the current three-drug regimen. Mebendazole
will be given in combination with carboplatin, vincristine, and temozolomide in cohorts of
three patients in an effort to determine if this four-drug combination is "well-tolerated".
The four-drug regimen will be considered "well-tolerated" if none or one of the initial
three-to-six enrolled patients has a severe adverse event related to therapy after one
induction cycle (10 weeks) of treatment.

In the phase II portion of the study, potential subjects will be offered the option to
participate in the study, to receive mebendazole with the three other drugs (CVT+M). Those
who do not wish to receive mebendazole will then be given the option to enroll as a control
and receive the three current drugs alone (CVT). Treatment will take place over a period of
70 weeks. After one cycle of induction chemotherapy (10 weeks duration), evaluation will be
performed to assess response. Patients with stable disease or decreasing tumor size will
continue maintenance therapy with an additional six 10-week maintenance cycles. Patients who
demonstrate progression following the induction cycle will be taken off-study to continue
treatment. Following completion of therapy, patients will be monitored to assess event-free
and overall survival. Data will be compared between the CVT+M and CVT treatment arms.

For the phase II portion of the study, the outcome variables of interest are
progression-free and overall survival. Survival will be estimated using the Kaplan-Meier
Product-Limit Method and compared using the log-rank test. Patients who are lost to
follow-up or who are alive at the end of the study will be considered 'censored' for the
survival analysis. Similarly, patients who have not progressed (or who have not died) as of
their last known follow-up, will be considered 'censored' for the time-to-progression

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 ≥

- 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

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally tolerated dose of Mebendazole in combination with Vincristine, Carboplatin, and Temozolomide

Outcome Description:

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.

Outcome Time Frame:

Assessed during the 10 week Induction cycle for each patient

Safety Issue:


Principal Investigator

Mark P Atlas, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

North Shore-LIJ


United States: Food and Drug Administration

Study ID:




Start Date:

June 2013

Completion Date:

December 2017

Related Keywords:

  • Pilomyxoid Astrocytoma
  • Pilocytic Astrocytoma
  • Glioma, Astrocytic
  • Optic Nerve Glioma
  • Pleomorphic Xanthoastrocytoma
  • pilomyxoid astrocytoma
  • Pilocytic Astrocytoma
  • Glioma
  • Optic Nerve Glioma
  • mebendazole
  • Pleomorphic Xanthoastrocytoma
  • Astrocytoma
  • Glioma
  • Optic Nerve Glioma



Cohen Children's Medical Center of New YorkNew Hyde, New York  11040