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

• ClinicalTrials.gov Identifier: NCT04696029
• Recruitment Status: Recruiting
• First Posted: January 6, 2021
• Last Update Posted: April 8, 2024
• Sponsor: Giselle Sholler
• Information provided by (Responsible Party): Giselle Sholler, Milton S. Hershey Medical Center

Study Description

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)

Study Design

• Study Type: Interventional (Clinical Trial)
• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Genevieve Bergendahl, MSN; 7175310003; gbergendahl@pennstatehealth.psu.edu

Locations

United States, Arkansas

Arkansas Children's Hospital; Recruiting

Little Rock, Arkansas, United States, 72202

Contact: Susan Hall 501-364-2760 HallSF@archildrens.org

Principal Investigator: Kevin Bielamowicz, MD

United States, California

UCSF Benioff Children's Hospital Oakland-; Recruiting

Oakland, California, United States, 94609

Contact: Group Contact PedOncRschOAK@ucsf.edu

Principal Investigator: Jennifer Michlitsch, MD

Rady Children's Hospital; Recruiting

San Diego, California, United States, 92123

Contact: Franchesca Ramirez 858-966-8155 framirez@rchsd.org

Principal Investigator: William Roberts, MD

United States, Connecticut

Connecticut Children's Hospital; Not yet recruiting

Hartford, Connecticut, United States, 06106

Contact: Nicole McCracken 860-545-9337 NMccracken@connecticutchildrens.org

Principal Investigator: Michael Isakoff, MD

United States, Florida

Arnold Palmer Hospital for Children; Recruiting

Orlando, Florida, United States, 32806

Contact: Michelle Pellet 321-841-8588 Michelle.Pellett@orlandohealth.com

Principal Investigator: Amy Smith, MD

St. Joseph's Children's Hospital; Recruiting

Tampa, Florida, United States, 33607

Contact: Jennifer Manns Jennifer.Manns@baycare.org

Principal Investigator: Don Eslin, MD

United States, Kentucky

Kentucky Children's Hospital; Recruiting

Lexington, Kentucky, United States, 40502

Contact: Brittany Fuller blfull2@email.uky.edu

Principal Investigator: Tom Badgett, MD

University of Louisville/Norton's Children's; Recruiting

Louisville, Kentucky, United States, 40202

Contact: Jennifer Miller Jennifer.Miller4@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; Recruiting

Kansas City, Missouri, United States, 64108

Contact: Nicole Harvey 816-302-6893 ndharvey@cmh.edu

Principal Investigator: Kevin Ginn, MD

Cardinal Glennon Children's Medical Center; Not yet recruiting

Saint Louis, Missouri, United States, 63104

Contact: Gina Martin, RN 314-268-4000 gina.martin@health.slu.edu

Principal Investigator: William Ferguson, MD

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact: Sherri Mayans sherri.mayans@hmhn.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: Thomas Russell, MD

United States, Pennsylvania

Penn State Milton S. Hershey Medical Center and Children's Hospital; 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; Recruiting

Charleston, South Carolina, United States, 29425

Contact: Shanta Salzar, MD 843-792-2957 salzers@musc.edu

Principal Investigator: Jaqueline Kraveka, MD

United States, Texas

Dell Children's Blood and Cancer Center; 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 Sholler

Investigators

• Study Chair: Michael A Huang, MD; Beat Childhood Cancer at Atrium Health

More Information

Additional Information:

Beat Childhood Cancer Consortium website 

• Responsible Party: Giselle Sholler, Beat Childhood Cancer Chair, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT04696029
• Other Study ID Numbers: BCC016
• First Posted: January 6, 2021
• Last Update Posted: April 8, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Medulloblastoma; Glioma; 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