Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA.
Clin Cancer Res. 2011 Feb 1;17(3):589-97. doi: 10.1158/1078-0432.CCR-10-0738. Epub 2010 Nov 29.
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.
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.
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.
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.
本试验的主要目的是定义和描述在难治性实体瘤或中枢神经系统（CNS）肿瘤患儿中，维持 100-150mcg/ml 或 150-200mcg/ml 谷浓度所需的口服丙戊酸（VPA）的毒性。次要目标包括评估稳态时外周血单核细胞（PBMC）中游离和总 VPA 药代动力学（PK）和组蛋白乙酰化。
口服 VPA 初始每日两次，随后每日三次给药，持续不断以维持 100-150mcg/ml 的谷浓度。研究了首剂量和稳态 PK。使用 ELISA 技术评估 PBMC 中组蛋白 H3 和 H4 的乙酰化。
共招募了 26 名儿童，其中 16 名可评估毒性。剂量限制的嗜睡和肿瘤内出血与 100-150mcg/ml 的 VPA 谷浓度相关。因此，最终的 6 名儿童接受 VPA 治疗以维持 75-100mcg/ml 的谷浓度，并未出现任何剂量限制毒性。首剂量和稳态 VPA PK 参数与以前报道的癫痫患儿相似。在研究的 50%患者中观察到 PBMC 组蛋白乙酰化增加。观察到 1 例部分缓解（多形性胶质母细胞瘤）和 1 例轻微缓解（脑干胶质瘤）。
每日三次给予 VPA 以维持 75-100mcg/ml 的谷浓度，在难治性实体瘤或 CNS 肿瘤患儿中耐受良好。在稳态时，一半的患者观察到 PBMC 中组蛋白过度乙酰化。应考虑将 VPA 与化疗和/或放疗联合用于未来的临床试验，尤其是针对 CNS 肿瘤。
