Phase II Trial of Eflornithine/DFMO as Maintenance Therapy for Molecular High Risk/Very High Risk and Relapsed/Refractory Medulloblastoma
Objective
Primary Objective: 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 Objectives: 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 progression free survival Overall Survival (OS) Response Rate for patients with non-bulky residual disease present. To develop a complete safety and tolerability profile of difluoromethylornithine (DFMO) in pediatric subjects with medulloblastoma. To measure CSF penetration after DFMO administration in pediatric subjects with medulloblastoma.
Exploratory Objective: Biological Correlates to include: Genomic Analysis of available patient tumors to evaluate the ODC/LIN28 pathway and targeted pathways to further correlate with response to treatment. In addition, established cell lines will be studied to evaluate treatment response in vitro for correlation with genomic sequencing analysis. Circulating tumor DNA (ctDNA) analysis of patient plasma samples as a biomarker of tumor disease burden and treatment response. Difluoromethylornithine (DFMO) will be used in an open label, single agent, multicenter, study for subjects with: 1) Molecular high risk/very high risk medulloblastoma that have completed conventional first line therapy 2) Relapsed/refractory medulloblastoma that have received at least 1 line of salvage therapy
In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 2500 mg/m2 BID (per dosing chart in Section 5.1) 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)
Cohort 1: Molecular High Risk Medulloblastoma: an increase in 2-year PFS from 65% to 85% - will require 32 evaluable subjects.
Cohorts 2: Molecular Very High Risk Medulloblastoma: an increase in 2-year PFS from 50% to 70% - will require 39 evaluable subjects.
Cohort 3: Relapsed/Refractory Medulloblastoma: an increase in 2-year PFS from 20% to 40% - will require 36 evaluable subjects.
