Abstract B81: Phase I/II trial of vorinostat in combination with etoposide in pediatric patients with relapsed/refractory solid tumors.
Authors: Trippett Tanya M. , Smith Amy , Neville Kathleen , Chi Susan , Narendran Aru , Arceci Robert , Direnzo Jennifer , Gore Lia 
Published: August 2014

Abstract
Introduction: Vorinostat has been shown to potentiate DNA damage induced by topoisomerase II inhibitors in a sequence dependent fashion. A multi-center, open label phase I study with escalating doses of vorinostat in combination with etoposide was conducted to establish the safety of the combination in pediatric patients with refractory solid tumors to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of this regimen.
Methods: Eligible patients were ≤21 years of age with relapsed/refractory solid tumors including central nervous system tumors. Study design consisted of a standard 3+3 dose escalation schema. Vorinostat was administered once daily for days 1-4 of the treatment cycle in escalating doses (125 mg/m2, 160 mg/m2, 210 mg/m2, and 270 mg/m2). Etoposide was administered at a fixed dose of 100 mg/m2/day on days 3-5 of the treatment cycle. Etoposide was administered 4 hours after administration of vorinostat. Each treatment cycle was 21 days. Intrapatient dose escalation was not permitted. The maximum tolerated dose (MTD) was defined as the highest dose level with an observed incidence of dose-limiting toxicity (DLT) in no more than one of six patients within the first treatment cycle. Histone acetylation, histone phosphorylation, and gene expression profiling were performed as correlative studies. Exploratory studies included assessment of symptom distress by self report in children between the ages of 10 and 18 with the MSAS (10-18) instrument.
Results: Twenty-one patients (CNS 12, neuroblastoma 6, Wilms’ tumor 1, rhabdomyosarcoma 1, hepatoblastoma 1) were enrolled on study and 19 patients were treated. Median age was 12 years (range 4-20 years); 11 males and 10 females with a median performance status 90% were included. One patient experienced a DLT (Gr 4 platelet count decreased) at the 1stdose level (125 mg/m2 vorinostat,100 mg/m2 etoposide). The predominant Grade 3 and 4 toxicities attributed to the combination included white blood cell count decreased (45%), neutrophil count decreased (55%), lymphocyte count decreased (30%), and platelet count decreased (25%). Grade 3-4 events in ≤10% of patients included anemia (10%), hypophosphatemia (5%), and infection (5%). Stable disease was reported in 4 patients (CNS 3, sarcoma 1). Biologic correlative studies and symptom distress data will be presented.
Conclusion: Vorinostat followed in combination with etoposide was found to be safe and well tolerated in children with refractory solid tumors. The recommended phase II dose was established at vorinostat 270 mg/m2 and etoposide 100 mg/m2 and will be evaluated in an ongoing phase II study in pediatric patients with sarcoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B81.
Citation Format: Tanya M. Trippett, Amy Smith, Kathleen Neville, Susan Chi, Aru Narendran, Robert Arceci, Jennifer Direnzo, Lia Gore. Phase I/II trial of vorinostat in combination with etoposide in pediatric patients with relapsed/refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B81.