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DFMO as Maintenance Therapy for Molecular High/Very High Risk and Relapsed Medulloblastoma

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ClinicalTrials.gov Identifier: NCT04696029
Recruitment Status : Recruiting
First Posted : January 6, 2021
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
Giselle SaulnierSholler, Atrium Health

Brief Summary:
Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study as Maintenance Therapy for Molecular High Risk/Very High Risk and Relapsed/Refractory Medulloblastoma.

Condition or disease Intervention/treatment Phase
Medulloblastoma Drug: Difluoromethylornithine Phase 2

Detailed Description:

In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 2500 mg/m2 BID on each day of study.

Subjects will be evaluated in 3 Cohorts:

Cohort 1: Molecular High Risk Medulloblastoma Cohort 2: Molecular Very High Risk Medulloblastoma Cohort 3: Relapsed/Refractory Medulloblastoma

A total of 118 subjects across all cohorts will be enrolled to ensure that there will be 107 evaluable subjects (32-39 per cohort)

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Study Type : Interventional
Estimated Enrollment : 118 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Eflornithine/DFMO as Maintenance Therapy for Molecular High Risk/Very High Risk and Relapsed/Refractory Medulloblastoma
Actual Study Start Date : March 29, 2021
Estimated Primary Completion Date : March 2028
Estimated Study Completion Date : March 2029


Arm Intervention/treatment
Experimental: Difluoromethylornithine (DFMO)
study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 2500 mg/m2 BID on each day of study.
Drug: Difluoromethylornithine

DFMO (difluoromethylornithine is an inhibitor of ornithine decarboxylase (ODC) designated chemically as 2-(difluoromethyl)-DL-ornithine monohydrochloride monohydrate.

The dosage form to be used in this study is provided as a convex tablet containing 192 mg eflornithine (equivalent to 250 mg of eflornithine HCl, monohydrate). The tablets are packaged and sealed in opaque white HDPE bottles, and each bottle contains 100 tablets. The DMFO tablets are supplied by USWorldMeds (USWM).

The tablets are to be stored at room temperature (20-250C).

Other Names:
  • Eflornithine
  • DFMO




Primary Outcome Measures :
  1. Number of participants with event free survival (EFS) during study [ Time Frame: 2 years plus 5 years follow up ]
    o To evaluate the efficacy of difluoromethylornithine (DFMO) as a single agent in preventing relapse in patients with molecular high risk and very high risk medulloblastoma, and relapsed/refractory medulloblastoma based upon the 2-year progression-free survival rate (PFS) compared to relevant historical controls.


Secondary Outcome Measures :
  1. Length of time that participants experience Overall Survival (OS) [ Time Frame: 7 years ]
    o To evaluate the efficacy of difluoromethylornithine (DFMO) as a single agent in patients with molecular high risk and very high risk medulloblastoma, and relapsed/refractory medulloblastoma based upon overall survival

  2. Determine the Overall Response Rate (ORR) of Participants using Modified RANO Criteria [ Time Frame: 2 years ]
    To evaluate the efficacy of difluoromethylornithine (DFMO) as a single agent in patients with molecular high risk and very high risk medulloblastoma, and relapsed/refractory medulloblastoma based upon Response Rate for patients with non-bulky residual disease present.

  3. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years plus 30 days ]
    To develop a complete safety and tolerability profile of difluoromethylornithine (DFMO) in pediatric and young adult subjects with medulloblastoma.

  4. Determine amount of DFMO in the CSF at 3 hours post dose [ Time Frame: 2 years ]
    o To measure CSF penetration after DFMO administration in pediatric subjects with medulloblastoma



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: 0-21 years of age at diagnosis
  2. Pathology All patients must either have a pathologically confirmed diagnosis of medulloblastoma with molecular grouping identified by either Nanostring or methylation profiling.

    Cohort 1- Molecular High Risk:

    • Metastatic non-MYC amplified Group 3
    • Metastatic Group 4
    • Metastatic non-WNT/non-SHH (Must be non-MYC amplified)

    Cohort 2- Molecular Very High Risk

    • Metastatic OR MYCN amplified OR TP53 mutant non-infant (>3 yrs) SHH
    • MYC amplified Group 3
    • Non-WNT, non-SHH infant (< 3 yrs)

    Cohort 3: Relapsed/Refractory Medulloblastoma

  3. Pre-enrollment tumor survey:

    Prior to enrollment on this study, a determination of mandatory disease staging must be performed:

    • Tumor imaging studies including: Brain and spine MRI
    • Lumbar Puncture only if previously positive
    • Bone Marrow aspiration/biopsy only if previously positive
    • This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to first dose of study drug, but must be done within a maximum of 4 weeks before first dose of study drug.
  4. Disease Status: Subjects must have no evidence of disease, or stable* residual nonbulky** disease.

    *Stable residual disease defined as non-progression over 2 separate imaging studies at least 6 weeks apart

    **Non-bulky disease defined as maximal cross-sectional area < 3cm^2 at enrollment. Patients with leptomeningeal disease are allowed to participate on study.

  5. Timing from prior therapy:

    Enrollment (first dose of DFMO) no later than 60 days after last dose of conventional chemotherapy. Patients who have undergone high dose chemotherapy (HDCT) with autologous stem cell transplantation (SCT) are eligible if more than 45 days have elapsed since date of last SCT.

  6. Patients must have a Lansky or Karnofsky Performance Scale score of ≥ 50% (see Appendix II) and patients must have a life expectancy of ≥ 2 months.
  7. 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.
  8. Patients must have adequate organ functions at the time of registration:

    • Hematological: Hematological recovery as defined by ANC ≥750/μL, platelets ≥30 (non-transfused x 7 days)
    • Liver: Adequate liver function as defined by AST and ALT <10x upper limit of normal
    • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum creatinine based on age/gender
  9. 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.
  10. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria:

  1. BSA of <0.25 m2
  2. Metastatic disease outside of CNS
  3. Relapsed/refractory patients who are radiation-naïve and age 5 years or older at time of enrollment
  4. Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
  5. Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior chemotherapy.
  6. 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.
  7. 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): NCT04696029


Contacts
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Contact: Genevieve Bergendahl, MSN 704.355.1220 genevieve.bergendahl@atriumhealth.org
Contact: Sharon McKee 704.355.1220 sharon.mckee@atriumhealth.org

Locations
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United States, Arkansas
Arkansas Children's Hospital Not yet recruiting
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- Not yet recruiting
Oakland, California, United States, 94609
Contact: Effie Bourgin       EBourgin@mail.cho.org   
Principal Investigator: Anurag Agrawal, MD         
United States, Connecticut
Connecticut Children's Hospital Not yet recruiting
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 Not yet recruiting
Orlando, Florida, United States, 32806
Contact: Jessica El-Shami    321-841-8588    Jessica.El-Shami@orlandohealth.com   
Principal Investigator: Don Eslin, MD         
St. Joseph's Children's Hospital Not yet recruiting
Tampa, Florida, United States, 33607
Contact: Jennifer Manns       Jennifer.Manns@baycare.org   
Contact: Connie Nickerson       connie.nickerson@baycare.org   
Principal Investigator: Don Eslin, MD         
United States, Kentucky
Norton Children's Hospital/University of Louisville Not yet recruiting
Louisville, Kentucky, United States, 40202
Contact: Jennifer Thomas       Jennifer.Thomas@nortonhealthcare.org   
Contact: Michael A Huang, MD    502.852.8450    michael.huang@louisville.edu   
Principal Investigator: Huang A Michael, MD         
United States, Missouri
Children's Mercy Hospitals and Clinics Not yet recruiting
Kansas City, Missouri, United States, 64108
Contact: Michelle Dinkins    816-302-6893    MDinkins@cmh.edu   
Principal Investigator: Keith August, MD         
Cardinal Glennon Children's Medical Center Not yet recruiting
Saint Louis, Missouri, United States, 63104
Contact: Katherine Maxwell, RN    314-268-4000      
Principal Investigator: William Ferguson, MD         
United States, New Jersey
Hackensack University Medical Center Not yet recruiting
Hackensack, New Jersey, United States, 07601
Contact: Chreyl Falls       Cheryl.Falls@hackensackmeridian.org   
Principal Investigator: Derek Hanson, MD         
United States, North Carolina
Levine Children's Hospital Recruiting
Charlotte, North Carolina, United States, 28204
Contact: Jontyce Green    980-442-2356    Jontyce.Green@AtriumHealth.org   
Principal Investigator: Javier Oesterheld, MD         
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center and Children's Hospital Not yet recruiting
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 Not yet recruiting
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 Not yet recruiting
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 SaulnierSholler
Investigators
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Study Chair: Michael A Huang, MD Beat Childhood Cancer at Atrium Health
Additional Information:
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Responsible Party: Giselle SaulnierSholler, Beat Childhood Cancer Chair, Atrium Health
ClinicalTrials.gov Identifier: NCT04696029    
Other Study ID Numbers: BCC016
First Posted: January 6, 2021    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021
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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Glioma
Medulloblastoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
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