This phase I trial is studying the side effects and best dose of ABT-888 when given in combination with temozolomide in treating young patients with recurrent or refractory CNS tumors. ABT-888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving ABT-888 together with temozolomide may kill more tumor cells.
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of ABT-888 in combination with temozolomide in children with recurrent or refractory CNS tumors. II. To study the plasma pharmacokinetics (PK) of ABT-888 and PARP inhibition in peripheral blood mononuclear cells (PBMC) in order to recommend a Phase 2 dose of ABT-888 in combination with temozolomide in children with recurrent or refractory CNS tumors. III. To describe the toxicities of the combination of ABT-888 and temozolomide in children with recurrent or refractory CNS tumors. SECONDARY OBJECTIVES: I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMC) prior to and following ABT-888 administration. II. To assess PARP expression and/or activity in tumor tissue obtained at either initial diagnosis or relapse. III. To determine expression and/or activity of DNA repair pathways, including MGMT and mismatch repair, in tumor tissues, when available. IV. To document, within the confines of this phase 1 trial, radiographic tumor response to ABT-888 and temozolomide. OUTLINE: This is a dose-escalation study of ABT-888. Patients receive oral ABT-888 twice daily and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 13-26 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected for pharmacokinetics and further laboratory analysis.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Pediatric Brain Tumor Consortium
Memphis, Tennessee, United States
MTD or recommended phase II dose of veliparib
Time frame: 28 days
Acute toxicities
These toxicities will be tabulated according to dose level.
Time frame: Initial 4 weeks (course 1)
Chronic toxicities
Tabulated according to dose level and course of therapy.
Time frame: Up to 30 days post-treatment
Plasma drug concentrations and pharmacokinetic parameters, including volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC)
Presented in tabular and graphical form, and estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance (ANOVA) on dose-normalized parameters.
Time frame: Baseline and during course 1
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