Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report

Abstract

Purpose: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state.

Patients and methods: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique.

Results: Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed.

Conclusions: VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors.

©2010 AACR.

Figures

Figure 1

Figure 1A This figure demonstrates a lack of correlation between valproic acid dose and steady state total valproic acid concentration. Patients receiving valproic acid twice daily required more dose escalations and higher final doses to achieve targeted concentrations than those receiving the drug three times daily. Css = steady state concentration; VPA = valproic acid; SD = standard deviation; TID = three times daily; BID = twice daily. Figure 1B This figure illustrates the relationship between free valproic acid and total valproic acid concentrations. Fifty seven paired measurements of valproic acid concentration from 22 patients were included in this figure. Each data point represents the mean value of measurements from a single patient. VPA = valproic acid; SD = standard deviation.

Figure 1

Figure 1A This figure demonstrates a lack of correlation between valproic acid dose and steady state total valproic acid concentration. Patients receiving valproic acid twice daily required more dose escalations and higher final doses to achieve targeted concentrations than those receiving the drug three times daily. Css = steady state concentration; VPA = valproic acid; SD = standard deviation; TID = three times daily; BID = twice daily. Figure 1B This figure illustrates the relationship between free valproic acid and total valproic acid concentrations. Fifty seven paired measurements of valproic acid concentration from 22 patients were included in this figure. Each data point represents the mean value of measurements from a single patient. VPA = valproic acid; SD = standard deviation.