This phase I/II trial studies the side effects and best dose of vorinostat and to see how well it works when given together with radiation therapy followed by maintenance therapy with vorinostat in treating younger patients with newly diagnosed diffuse intrinsic pontine glioma (a brainstem tumor). Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with radiation therapy may kill more tumor cells.
PRIMARY OBJECTIVES: l. To estimate the maximum tolerated dose (MTD) or recommend a phase 2 dose of vorinostat given concurrently with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). II. To define and describe the toxicities of vorinostat given concurrently with radiation in children with newly diagnosed DIPG. III. To determine, in the context of this phase I/II trial, the anti-tumor activity of combining vorinostat with radiation, followed by maintenance vorinostat for twelve courses, in children with newly diagnosed DIPG, as measured by 12-month event-free survival (EFS) and overall survival (OS). IV. To determine the toxicities of vorinostat for 12 additional courses after completion of vorinostat and radiation. SECONDARY OBJECTIVES: I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMCs) before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation. II. To measure histone deacetylase 2 (HDAC2) levels and assess histone acetylation in PBMCs before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation. III. To quantify deoxyribonucleic acid (DNA) repair proteins from the NHEJ and homologous recombination repair (HHR) pathways in tumors by either Western analysis or immunohistochemistry, if paraffin-embedded tumor is available. OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study. Patients receive vorinostat orally (PO) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients undergo 3-dimensional (3D) conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. Patients then receive maintenance therapy comprising vorinostat PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
79
Undergo 3D conformal radiation therapy
Undergo intensity-modulated radiation therapy
Correlative studies
Given PO
Children's Hospital of Alabama
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Providence Hospital
Mobile, Alabama, United States
Arkansas Children's Hospital
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Maximum Tolerated Dose (MTD) of Vorinostat
The dose of vorinostat in mg/sqm/day to be administered with combination chemotherapy and radiation therapy
Time frame: Planned 7 weeks during chemoradiotherapy
Event-Free Survival
Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first.
Time frame: 2 years after study enrollment
Incidence of Toxicity During Chemoradiation Therapy
Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience
Time frame: Planned 7 weeks during chemoradiotherapy
Incidence of Toxicity During Maintenance Therapy
Proportion of patients who experience any grade 3 or higher CTC AE Version 4 adverse experience
Time frame: Planned 12 months of maintenance with Vorinostat
Overall Survival
Time from enrollment to death or last follow-up, whichever occurs first.
Time frame: 2 years after study enrollment
Change in H3 and H4 Acetylation Levels in PBMCs
Degree of acetylation in peripheral blood monocytes will be divided into quartiles and coded as none, mild, moderation or marked.
Time frame: Baseline to up to 7 weeks
Change in NHEJ Activity in PBMCs
Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points.
Time frame: Baseline to up to 7 weeks
Levels of DNA Repair Proteins in Paraffin-embedded Blocks, Measured Via Immunohistochemistry or Western Analysis
For immunohistochemistry from tumor blocks, the intensity will be graded from 1 to 3; for Western analysis, a percentage of the intensity relative to the tumor with the highest level will be measured.
Time frame: Baseline
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