Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether nifurtimox in combination with cyclophosphamide and topotecan are effective in the treatment of relapsed or refractory neuroblastoma and medulloblastoma.

Detailed Description
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This study is being done to test the effect of a drug, nifurtimox, against neuroblastoma and medulloblastoma in children. Nifurtimox is a drug that has been used in South America for many years to treat a parasitic disease known as Chagas Disease. It is not approved by the Food and Drug Administration for routine use in neuroblastoma or medulloblastoma in the United States, but limited early observations suggest that nifurtimox may have anti tumor activity for neuroblastoma and medulloblastoma. From the preliminary trials of nifurtimox we have determined a safely tolerated dose of nifurtimox to use in neuroblastoma patients (30mg/kg/day). The dose determined in the Phase I study to be safe, will be the dose used for this study. From clinical experience in South America, we know that children can tolerate nifurtimox when given by mouth, and it appears to have no long-term side effects when used to treat Chagas Disease. Based on our laboratory and animal studies, we believe that drug levels similar to those used to treat Chagas Disease may shrink/kill neuroblastoma cells, especially when combined with other chemotherapy drugs. We do not know whether nifurtimox will shrink/kill tumor cells effectively in children. Therefore, the major goal of the study is to learn if nifurtimox in combination with other chemotherapy drugs is effective in shrinking/killing neuroblastoma and medulloblastoma cells.

Official Title
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A Phase II Trial of Nifurtimox for Refractory or Relapsed Neuroblastoma or Medulloblastoma.

Conditions
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Neuroblastoma, Medulloblastoma

Intervention / Treatment
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* Drug: Nifurtimox
* Drug: Cyclophosphamide
* Drug: Topotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 0-21 years at the time of diagnosis. Diagnosis: Histologic verification at either the time of original diagnosis or relapse of neuroblastoma or medulloblastoma. Disease Status: Refractory or first or multiple relapsed neuroblastoma, or medulloblastoma that has relapsed after, or is refractory to, a chemotherapy-containing treatment regimen. Measurable disease, including at least one of the following: Measurable tumor by CT or MRI For neuroblastoma patients only, a positive MIBG (MIBG not required if subject's neuroblastoma is previously determined to not uptake MIBG), abnormal urinary catecholamine levels, or positive bone marrow biopsy/aspirate. For medulloblastoma patients only, positive CSF cytology Current disease state must be one for which there is currently no known curative therapy. A negative urine pregnancy test is required for female participants of child bearing potential (≥13 years of age). Organ Function Requirements Patients without bone marrow metastases must have an ANC > 500/μl and platelet count >50,000/μl. Patients must have adequate liver function as defined by AST or ALT <10x normal Informed Consent: All patients and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines Exclusion Criteria: Life expectancy <2 months or Lansky score <50% Investigational Drugs: Patients who are currently receiving another investigational drug are excluded from participation. Anti-cancer Agents: Patients who are currently receiving other anticancer agents are not eligible. Patients must have fully recovered from the effects of prior chemotherapy, generally at least 3 weeks from the most recent administration (6 weeks for nitrosoureas). Infection: Patients who have an uncontrolled infection are not eligible until the infection is judged to be well controlled. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded. Compensation for travel related expenses may be available

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nifurtimox<br> | Drug: Nifurtimox<br>* 30mg/kg/day PO divided into TID dosing q day<br>* Other names: Lampit;Drug: Cyclophosphamide<br>* 250 mg/m2/dose in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.<br>* Other names: Cytoxan;Drug: Topotecan<br>* 0.75mg/m2/dose, in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.<br>* Other names: Hycamptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Related Adverse Events as a Measure of Safety and Tolerability | Test the safety of nifurtimox in children with relapsed or refractory neuroblastoma or medulloblastoma in combination with cyclophosphamide/topotecan | 2 years | 
| Best Radiological Response in Participants Using the RECIST Criteria | Test the efficacy of nifurtimox in children with relapsed or refractory neuroblastoma or medulloblastoma in combination with cyclophosphamide/topotecan Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, Overall Best Response assessed by CT or MRI, MIBG, and Bone Marrow: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions, bone marrow with CR, and MIBG with CR/PR. Overall Response (OR) = CR + PR. | 2 years |