Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma

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

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.

Study Overview

• Status: Completed
• Conditions: Medulloblastoma; Neuroblastoma
• Intervention / Treatment: Drug: Nifurtimox; Drug: Cyclophosphamide; Drug: Topotecan

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Hospital
  • Florida
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children- MD Anderson
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Kapiolani Medical Center for Women and Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital and Clinics on Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center and Children's Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer and Hematology Centers
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the correlation between the pharmacologic serum levels of nifurtimox (in combination with cyclophosphamide and topotecan) with tumor response.	2 years
Quality of life and neurocognitive evaluation/questionnaire.	2 years
Biology studies to include: genomic analysis of cells pre- and post- treatment, correlation of in vitro response to in vivo response, flow cytometry of tumor burden in bone marrow and biomarker development.	2 years

Collaborators and Investigators

• Sponsor: Giselle Sholler
• Collaborators: Bayer
• Investigators: Study Chair: Giselle Sholler, MD, Beat Childhood Cancer at Atrium Health

Publications and helpful links

Helpful Links

• Beat Childhood Cancer Consortium website

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2008
• Primary Completion (Actual): April 28, 2020
• Study Completion (Actual): October 28, 2022

Study Registration Dates

• First Submitted: January 14, 2008
• First Submitted That Met QC Criteria: January 24, 2008
• First Posted (Estimated): January 25, 2008

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: August 2, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Medulloblastoma; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Topoisomerase I Inhibitors; Trypanocidal Agents; Cyclophosphamide; Topotecan; Nifurtimox
• Other Study ID Numbers: V0706