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Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04301843
Recruitment Status : Not yet recruiting
First Posted : March 10, 2020
Last Update Posted : April 17, 2020
Sponsor:
Collaborators:
KC Pharma
Beat NB Cancer Foundation
Information provided by (Responsible Party):
Giselle Sholler, Spectrum Health Hospitals

Brief Summary:
Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Eflornithine Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

  • Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
  • Arm 3: Subjects who are relapsed or refractory with active disease.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 131 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : April 1, 2025
Estimated Study Completion Date : April 1, 2030


Arm Intervention/treatment
Experimental: Eflornithine (DFMO)

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Etoposide will be given at 50 mg/m2/dose PO daily for the first 14 days of each 21 days until 6 cycles of etoposide are completed.

DFMO (difluoromethylornithine) will be given at a dose of 1000 mg/m2 BID on each day of study.

Drug: Eflornithine
DFMO (difluoromethylornithine) will be given at a dose of 1000 mg/m2 BID on each day of study.
Other Names:
  • DFMO
  • difluoromethylornithine




Primary Outcome Measures :
  1. Number of participants with event free survival (EFS) during study [ Time Frame: 2 years plus 5 years follow up ]

    To evaluate the efficacy of difluoromethylornithine (DFMO) in combination with etoposide in patients with relapsed/refractory neuroblastoma, based upon:

    o Event free survival (EFS) from time of enrollment.



Secondary Outcome Measures :
  1. Length of time that participants experience Overall Survival (OS) [ Time Frame: 7 years ]

    To evaluate the efficacy of difluoromethylornithine (DFMO) in combination with etoposide in patients with relapsed/refractory neuroblastoma, based upon:

    o Overall Survival (OS) from time of enrollment.


  2. Determine the Overall Response Rate (ORR) of Participants using INSS Response Evaluation Criteria. [ Time Frame: 2 years ]

    To evaluate the efficacy of difluoromethylornithine (DFMO) in combination with etoposide in patients with relapsed/refractory neuroblastoma, based upon:

    o Response Rate for patients with active disease (Arm 3) using International Neuroblastoma Staging System (INSS) Response Evaluation Criteria.


  3. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years plus 30 days ]
    To monitor the safety and tolerability profile of difluoromethylornithine (DFMO) in combination with etoposide in pediatric and young adult patients with relapsed/refractory neuroblastoma.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 31 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
  • All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
  • Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

  • Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.
  • Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

    1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
    2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
    3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
    4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
    5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
    6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
    7. Stem Cell Transplant:

      1. Allogeneic: No evidence of active graft vs. host disease
      2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
    8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
  • Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
  • Life expectancy > 2 months
  • All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.
  • Subjects must have adequate organ functions at the time of registration:

    • Hematological: Total absolute neutrophil count ANC ≥750/μL
    • Liver: Subjects must have adequate liver function as defined by AST and ALT <5x upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
    • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
  • Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
  • Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria:

  • BSA of <0.25 m2.
  • Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
  • Subjects that received a dose of DFMO in combination with etoposide are not eligible.
  • 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 hematological and bone marrow suppression effects of prior chemotherapy.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04301843


Contacts
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Contact: Genevieve Bergendahl, MSN 6162670335 genevieve.bergendahl@helendevoschildrens.org
Contact: Shari McKee 6162670334 sharon.mckee@helendevoschildrens.org

Locations
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United States, Arkansas
Arkansas Children's Hospital
Little Rock, Arkansas, United States, 72202
Contact: Susan Hall    501-364-2760    HallSF@archildrens.org   
Principal Investigator: Kathleen Neville, MD         
United States, California
UCSF Benioff Children's Hospital Oakland-
Oakland, California, United States, 94609
Contact: Effie Bourgin       EBourgin@mail.cho.org   
Principal Investigator: Anurag Agrawal, MD         
Rady Children's Hospital
San Diego, California, United States, 92123
Contact: Mehrzad Milburn    858-966-8155      
Principal Investigator: William Roberts, MD         
United States, Connecticut
Connecticut Children's Hospital
Hartford, Connecticut, United States, 06106
Contact: Amy Newton    860-545-9337    ANewton@connecticutchildrens.org   
Principal Investigator: Michael Isakoff, MD         
United States, Florida
Arnold Palmer Hospital for Children
Orlando, Florida, United States, 32806
Contact: Jessica El-Shami    321-841-8588    Jessica.El-Shami@orlandohealth.com   
Principal Investigator: Don Eslin, MD         
United States, Hawaii
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, United States, 96813
Contact: Andrea Siu, MPH    808-535-7169    andrea.siu@kapiolani.org   
Principal Investigator: Randal Wada, MD         
United States, Minnesota
Children's Hospital and Clinics on Minnesota
Minneapolis, Minnesota, United States, 55404
Contact: Courtney Haller    612-813-5913    courtney.haller@childrensmn.org   
Principal Investigator: Jawhar Rawwas, MD         
United States, Missouri
Cardinal Glennon Children's Medical Center
Saint Louis, Missouri, United States, 63104
Contact: Katherine Maxwell, RN    314-268-4000      
Principal Investigator: William Ferguson, MD         
United States, North Carolina
Levine Children's Hospital
Charlotte, North Carolina, United States, 28204
Contact: Kimberly McKinney    980-442-2312    Kimberly.McKinney@carolinashealthcare.org   
Principal Investigator: Javier Oesterheld, MD         
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center and Children's Hospital
Hershey, Pennsylvania, United States, 17033
Contact: Suzanne Treadway       streadway@hmc.psu.edu   
Principal Investigator: Valerie Brown, MD         
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
Contact: Sydney Bargeloh    843-792-2957    BROWNSY@musc.edu   
Principal Investigator: Jaqueline Kraveka, MD         
United States, Texas
Dell Children's Blood and Cancer Center
Austin, Texas, United States, 78723
Contact: Rhea Robinson, RN    512-628-1902    TXAUS-DL-SFCHemonc.research@ascension.org   
Principal Investigator: Virginia Harrod, MD         
Sponsors and Collaborators
Giselle Sholler
KC Pharma
Beat NB Cancer Foundation
Investigators
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Study Chair: Giselle Sholler, MD Beat Childhood Cancer
Additional Information:
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Responsible Party: Giselle Sholler, Chair, Beat Childhood Cancer, Spectrum Health Hospitals
ClinicalTrials.gov Identifier: NCT04301843    
Other Study ID Numbers: BCC015
First Posted: March 10, 2020    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Eflornithine
Antineoplastic Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Ornithine Decarboxylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action