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

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

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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: DFMO

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • 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
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital Johns Hopkins Medicine
  • 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
  • New York
    • Bronx, New York, United States, 10467
      • The Children's Hospital at Montefiore
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide 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
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carrell Jr. Children's Hospital at Vanderbilt
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Blood and Cancer Center
    • 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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• 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: DFMO twice daily; 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; 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.; Other Names: Difluoromethylornithine; eflornithine HCl

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Giselle Sholler
• Collaborators: Beat NB Cancer Foundation; Because of Ezra; K C Pharmaceuticals Inc.
• Investigators: Study Chair: Giselle Saulnier-Sholler, MD, Beat Childhood Cancer

Publications and helpful links

General Publications

• Urban-Wojciuk Z, Graham A, Barker K, Kwok C, Sbirkov Y, Howell L, Campbell J, Woster PM, Poon E, Petrie K, Chesler L. The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme. Cancer Gene Ther. 2022 Jul;29(7):940-950. doi: 10.1038/s41417-021-00386-6. Epub 2021 Sep 14.
• Batth IS, Dao L, Satelli A, Mitra A, Yi S, Noh H, Li H, Brownlee Z, Zhou S, Bond J, Wang J, Gill J, Sholler GS, Li S. Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients. Int J Cancer. 2020 Dec 15;147(12):3550-3559. doi: 10.1002/ijc.33140. Epub 2020 Jun 23. Erratum In: Int J Cancer. 2021 Mar 15;148(6):E6.
• Lewis EC, Kraveka JM, Ferguson W, Eslin D, Brown VI, Bergendahl G, Roberts W, Wada RK, Oesterheld J, Mitchell D, Foley J, Zage P, Rawwas J, Rich M, Lorenzi E, Broglio K, Berry D, Saulnier Sholler GL. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma. Int J Cancer. 2020 Dec 1;147(11):3152-3159. doi: 10.1002/ijc.33044. Epub 2020 May 24.

Helpful Links

• Beat Childhood Cancer Consortium website

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2015
• Primary Completion (Actual): March 27, 2018
• Study Completion (Actual): August 24, 2023

Study Registration Dates

• First Submitted: March 5, 2015
• First Submitted That Met QC Criteria: March 20, 2015
• First Posted (Estimated): March 23, 2015

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Refractory Neuroblastoma; Neuroblastoma in remission; Relapsed Neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Ornithine Decarboxylase Inhibitors; Eflornithine
• Other Study ID Numbers: NMTRC003B