Neuroblastoma, Medulloblastoma
Conditions
Brief summary
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
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.
Interventions
DRUGNifurtimox
30mg/kg/day PO divided into TID dosing q day
DRUGCyclophosphamide
250 mg/m2/dose in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.
DRUGTopotecan
0.75mg/m2/dose, in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.
Sponsors
Bayer
Giselle Sholler
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Related Adverse Events as a Measure of Safety and Tolerability | 2 years | Test the safety of nifurtimox in children with relapsed or refractory neuroblastoma or medulloblastoma in combination with cyclophosphamide/topotecan |
| Best Radiological Response in Participants Using the RECIST Criteria | 2 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nifurtimox Nifurtimox: 30mg/kg/day PO divided into TID dosing q day
Cyclophosphamide: 250 mg/m2/dose in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.
Topotecan: 0.75mg/m2/dose, in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle. | 112 |
| Total | 112 |
Baseline characteristics
| Characteristic | Nifurtimox |
|---|---|
| Age, Continuous | 5.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 89 Participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 19 / 110 |
| other Total, other adverse events | 45 / 110 |
| serious Total, serious adverse events | 25 / 110 |
Outcome results
Primary
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.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nifurtimox | Best Radiological Response in Participants Using the RECIST Criteria | Complete Response | 7 Participants |
| Nifurtimox | Best Radiological Response in Participants Using the RECIST Criteria | Partial Response | 11 Participants |
| Nifurtimox | Best Radiological Response in Participants Using the RECIST Criteria | Stable Disease | 35 Participants |
| Nifurtimox | Best Radiological Response in Participants Using the RECIST Criteria | Progressive Disease | 23 Participants |
Primary
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
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nifurtimox | Number of Participants With Related Adverse Events as a Measure of Safety and Tolerability | 45 Participants |