Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

Abstract

In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

“…Furthermore, SAHA was recently approved by the Food and Drug Administration for treatment of cutaneous T-cell lymphoma. Pediatric Phase 1 trials have shown that SAHA (at 230 mg/m 2 /day) is well-tolerated in children with solid tumors ( 98 ). The in vivo dose of SAHA (50 mg/kg) showing protection in animal models of infl ammation translates to 6 mg/kg (total dose of 120 mg/day or 150 mg/m 2 for a 20 kg human child) , which is much lower than the maximum dose administered safely in pediatric patients ( 98 ).…”

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

“…We have previously shown that HDACi are able to limit the expansion of B-cell precursor (BCP)-ALL cells in vivo (4). The inclusion of HDACi into current ALL chemotherapy concepts requires the identification of suitable combination partners, as first clinical trials achieved only limited therapeutic responses (5,6) while establishing a good tolerance of HDACi in pediatric patients with malignant diseases. So far, only additive or even antagonistic interactions have been observed after combined treatment with HDACi and different conventional cytostatic drugs in myeloid leukemia and T-ALL cells (7).…”

Prospects of targeted therapy of acute leukemias in children

“…Вслед за этим было проведено исследование фазы I среди детей, в ко-тором рассматривалось применение вориностата для лечения солидных опухолей и лейкоза. Проде-монстрирована удовлетворительная переносимость, хотя пациентам с рефрактерным лейкозом требова-лись более низкие дозы [43]. На данный момент во-риностат тестируют в рамках детского клинического исследования фазы II в сочетании с децитабином при лечении рецидивов ОЛЛ в попытке «перепрограмми-ровать» профиль экспрессии генов и восстановить их чувствительность к химиотерапии.…”