Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors
Condition: Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Germ Cell Tumors; Ewings Sarcoma; Non-rhabdomyosarcoma Soft Tissue Sarcoma; Osteosarcoma; Rhabdomyosarcoma
MeSH terms: Neoplasms; Sarcoma; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Wilms Tumor; Retinoblastoma; Rhabdoid Tumor; Hepatoblastoma; Sarcoma, Clear Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Simvastatin; Cyclophosphamide; Topotecan; Myeloid growth factor
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): The starting dose of simvastatin will be 140 mg/m^2/dose BID for 21 days for the first group. Dose escalation for subsequent groups will be 180 mg/m^2/dose BID, 225 mg/m^2/dose BID, and 290 mg/m^2/dose BID. If the maximum tolerated dose (MTD) has been exceeded at the first dose level, then the subsequent cohort of subjects will be treated at a dose of 100 mg/m2/dose BID (dose level 0). Simvastatin will be administered orally twice daily, approximately 12 hours apart. Feeding tube (nasogastric tube or gastrostomy tube, NOT a jejunum localized tube) administration is allowed. If a subject vomits a dose of simvastatin, it will not be repeated.; The dose of cyclophosphamide will be fixed at 250 mg/m^2/dose. Cyclophosphamide will be administered intravenously over 30 minutes once daily for 5 days every 21 days.; The dose of topotecan will be fixed at 0.75 mg/m^2/dose. Topotecan will be administered, after cyclophosphamide, intravenously over 30 minutes once daily for 5 days every 21 days.; Myeloid growth factor (G-CSF or pegylated G-CSF) will be initiated 24-48 hours after the completion of topotecan and cyclophosphamide for all subjects, which would be day 6 or 7. Myeloid growth factor should continue until the absolute neutrophil count is greater than 2,000/mm^3
Other intervention name(s): zocor; Cytoxan; Neosar; Hycamtin; Granulocyte colony-stimulating factor (G-CSF); pegylated granulocyte colony-stimulating factor
Intervention MeSH terms: Cyclophosphamide; Topotecan; Simvastatin; Lenograstim; Mitogens
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment