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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase 1 Study Using Simvastatin in Combination With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

Brief 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 Summary: 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.
Sponsor: Emory University

Current Primary Outcome:

• Maximum Tolerated Dose (MTD) of Simvastatin [ Time Frame: First treatment to toxicity (up to 24 months) ]
  MTD will be the maximum dose at which fewer than one-third of subjects experience dose-limiting toxicities (DLTs) during Cycle 1 of therapy.
• Number of Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 24 months ]

  DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to study drug:

  Non-hematological dose-limiting toxicity: Any Grade 3 or 4 non-hematological toxicity (excluding nausea, alanine transaminase (ALT) or aspartate aminotransferase (AST) that returns to baseline or ≤ grade 1 within 7 days of study drug interruption, fever, infection, hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia, or creatinine phosphokinase (CPK) elevation that returns to baseline or ≤ grade 1 within 7 days of study drug interruption), Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered sufficiently medically significant or sufficiently intolerable by subjects that it requires treatment interruption, or hematological dose-limiting toxicity, defined as neutropenia or thrombocytopenia that precludes initiation of the next cycle of therapy within 14 days of the scheduled start date.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Percentage of Participants With Overall Tumor Response (Response Rate) [ Time Frame: 24 months ]

  Response is defined as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumor (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions.

  Response rate (%) = (number of patients with CR+PR/number of patients)*100

• Change in Total Cholesterol Level [ Time Frame: Baseline, 24 months ]
  Change in serum total cholesterol level after treatment with simvastatin. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.
• Change in serum interleukin-6 (IL-6) level [ Time Frame: Baseline, 24 months ]
  Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the IL-6 will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.
• Change in soluble interleukin 6 receptor (sIL-6R) [ Time Frame: Baseline, 24 months ]
  Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the sIL-6r will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.
• Change in signal transducer and activator of transcription 3 (STAT-3) expression [ Time Frame: Baseline, 24 months ]
  Change in STAT-3 expression after treatment with simvastatin. STAT-3 will be measured using phospho-specific flow cytometry, or phospho-flow.
• Change in phospho-STAT3 expression [ Time Frame: Baseline, 24 months ]
  Change in phospho-STAT3 expression after treatment with simvastatin. Phospho-STAT3 expression will be measured using phospho-specific flow cytometry, or phospho-flow.

Original Secondary Outcome: Same as current

Information By: Emory University

Dates:
Date Received: February 24, 2015
Date Started: February 2015
Date Completion: February 2021
Last Updated: October 13, 2016
Last Verified: October 2016