Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

This is a Phase I trial with new experimental drugs such as simvastatin in combination with topotecan and cyclophosphamide in the hopes of finding a drug that may work against tumors that have come back or that have not responded to standard therapy. This study will define toxicity of high dose simvastatin in combination with topotecan and cyclophosphamide and evaluate for cholesterol levels and IL6/STAT3 pathway changes as biomarkers of patient response.

Chemotherapy resistance is a major cause of treatment failure in pediatric solid tumors. STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor that promotes tumor proliferation, metastasis and chemotherapy resistance. Pediatric solid tumors such as neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and central nervous system (CNS) tumors such as glioblastoma and medulloblastoma have aberrant STAT3 signaling. In neuroblastoma, bone marrow production of interleukin 6 (IL-6), a STAT3 activating cytokine, is associated with poor prognosis. Thus STAT3 and its cognate ligand, IL-6, are rational therapeutic targets in pediatric solid and CNS tumors. HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, or "statins", lower LDL (low density lipoprotein) cholesterol by inhibiting the rate-limiting step in cholesterol biosynthesis. Pleiotropic properties of statins have been found to not only contribute to lowering the risk of heart disease, but decrease the incidence of cancer as well, leading to their use in clinical trials for adult solid and CNS tumors. Statins have been shown to inhibit IL-6 mediated STAT3 activation to prevent the recruitment of pro-inflammatory cells to injured heart tissue in adult patients. Therefore, the investigators hypothesize that the HMG-CoA reductase inhibitor, simvastatin, will augment chemotherapy effects to improve survival of patients with refractory or relapsed pediatric solid and CNS tumors. This is a Phase I trial of simvastatin in combination with topotecan and cyclophosphamide for refractory and/or relapsed solid or CNS tumors of childhood, in which the investigators will define toxicity and evaluate cholesterol levels and IL6/STAT3 pathway changes as biomarkers of patient response.