Preventative Trial of Difluoromethylornithine (DFMO) in High Risk Patients With Neuroblastoma That is in Remission

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate a new investigational drug to prevent reoccurrence of neuroblastoma that is in remission. This study drug is called DFMO. The objectives of this study will be to monitor for safety and look at efficacy of DFMO. The safety of the proposed dosing regimen in this trial will be tested by an on-going risk/benefit assessment during the study. A patient benefiting from treatment, not progressing on therapy, and in the absence of any safety issues associated with DFMO may continue on treatment up to 27 cycles with the expectation that there will be an overall clinical benefit. The procedures involved in this study include Medical history, Physical exam, Vital signs (blood pressure, pulse, temperature), Blood tests, Urine tests, MRI or CT scan of the tumor(s), meta-iodobenzylguanidine (MIBG) scans, and Bone marrow aspirations. All of these tests and procedures are considered standard of care for this population. Drug administration is also part of this protocol, including an investigational new drug called DFMO. The proposed dosing regimen is an oral dose of DFMO tablets two times a day for each day while on study. There will be 27 cycles. Each cycle will be 28 days in length.

Official Title
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A Phase II Preventative Trial of DFMO (Eflornithine HCl) as a Single Agent in Patients With High Risk Neuroblastoma in Remission

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: DFMO


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 a previous relapse of high risk neuroblastoma. Disease Status: Neuroblastoma that is in remission First dose of study medication must be greater than 30 days from completion of cytotoxic and antibody therapy and less than 120 days from previous therapy A negative serum or urine pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age). Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives (the pill), an intrauterine device (IUD), levonorgestrel implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended. Absolute Neutrophil Count (ANC) > 500/μl and platelet count >50,000/μl Organ Function Requirements: Subjects must have adequate liver function as defined by: Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) <10x upper limit of normal Serum bilirubin must be ≤ 2.0 mg/dl Serum creatinine based on age/gender Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines Exclusion Criteria: Lansky score < 60% Body Surface Area (BSA) (m2) of <0.25 Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation. Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the effects of prior chemotherapy (hematological and bone marrow suppression effects). Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator. Subjects 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.

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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DFMO twice daily<br>Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle. | Drug: DFMO<br>* Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.<br>* Other names: Difluoromethylornithine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Event Free Survival (EFS) During Study. | To evaluate the preventative activity of DFMO as a single agent in patients that are in remission based on: Event free survival (EFS) | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival (OS) | To evaluate the preventative activity of DFMO as a single agent in patients with neuroblastoma who are in remission based on: Overall Survival (OS) | 2 Years | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | To continue to determine the safety and tolerability of DFMO as a single agent and in pediatric and young adult patients with high risk neuroblastoma that is in remission. | 2 years | 
| Test the Association of Survival With ODC1 Genotype | Tests (p-value) of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype. Blood: microRNA analysis as predictor of DFMO effect, ornithine decarboxylase (ODC) single nucleotide polymorphism (SNP) analysis in DNA isolated from nucleated cells | 2 years | 
| Peak Plasma Concentration (Cmax) | Pharmacokinetic assay Cmax/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days. | Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) | Pharmacokinetic assay AUC(0-6 hr)/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days | 0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days | 
| Time to Reach Peak Plasma Concentration (Tmax) | Pharmacokinetic assay- tmax, hr Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days | 0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroblastoma in remission, Relapsed Neuroblastoma, Refractory Neuroblastoma