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

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.

Inclusion Criteria:

- Subjects must have had histologic verification of malignancy at original diagnosis or
relapse. All subjects with relapsed or refractory solid tumors are eligible including
primary or metastatic CNS tumors. In the case of diffuse intrinsic pontine glioma
(DIPG), or optic pathway glioma, imaging findings consistent with these tumors will
suffice without the need for biopsy for histologic verification.

- Subjects must have either measurable (the presence of at least one lesion that can be
accurately measured in at least one dimension with the longest diameter at least 20
mm. With spiral CT scan, lesions must be at least 10 mm.) or evaluable disease (the
presence of at least one lesion that cannot be accurately measured in at least one
dimension. Such lesions may be evaluable by nuclear medicine techniques,
immunocytochemistry techniques, tumor markers or other reliable measures.)

- Subject's current disease state must be one for which there is no known curative
therapy.

- Karnofsky ≥ 60% for subjects > 16 years of age and Lansky ≥ 50 for subjects ≤ 16 years
of age

- Subjects must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy

1. Myelosuppressive chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea).

2. Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. Pegfilgrastim) or 7 days for short acting growth
factor. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur. The duration of this interval must be discussed with
the study chair.

3. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a
biologic agent. For agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during which
adverse events are known to occur. The duration of this interval must be
discussed with the study chair.

4. Immunotherapy: At least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines.

5. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose
of a monoclonal antibody.

6. external beam radiation therapy (XRT): At least 14 days after local palliative
XRT (small port); 6 weeks must have elapsed since treatment with therapeutic
doses of I131-meta-iodobenzylguanidine (MIBG); At least 150 days must have
elapsed if prior total body irradiation (TBI), craniospinal XRT, or if ≥ 50%
radiation of pelvis; At least 42 days must have elapsed if other substantial bone
marrow (BM) radiation.

7. Stem Cell Infusion without TBI: No evidence of active graft vs. host disease and
at least 84 days must have elapsed after transplant and 42 days for autologous
stem cell infusion after I131-MIBG therapy.

8. Subjects must not have received any prior therapy with simvastatin.

- Adequate Bone Marrow Function Defined as:

1. For subjects with solid tumors without known bone marrow involvement: Peripheral
absolute neutrophil count (ANC) ≥ 750/mm3, Platelet count ≥ 75,000/mm3
(transfusion independent, defined as not receiving platelet transfusions for at
least 7 days prior to enrollment)

2. Subjects with known bone marrow metastatic disease will be eligible for study
provided they meet the blood counts in a. (may receive transfusions provided they
are not known to be refractory to red cell or platelet transfusions). These
subjects will not be evaluable for hematologic toxicity. If dose-limiting
hematologic toxicity is observed, all subsequent subjects enrolled must be
evaluable for hematologic toxicity.

- Adequate Renal Function Defined as:

1. Creatinine clearance or radioisotope glomerular filtration rate (GFR)
70ml/min/1.73 m^2 or

2. A serum creatinine based on age/gender as follows:

- Age: 1 to < 2 years; Male and female serum creatinine: 0.6 mg/dL

- 2 to < 6 years; Male and female serum creatinine: 0.8 mg/dL

- 6 to < 10 years; Male and female serum creatinine: 1.0 mg/dL

- 10 to < 13 years; Male and female serum creatinine: 1.2 mg/dL

- 13 to < 16 years; Male serum creatinine: 1.5 mg/dL and female serum creatinine: 1.4
mg/dL

- ≥ 16 years; Male serum creatinine: 1.7 mg/dL and female serum creatinine: 1.4 mg/dL

- Adequate Liver Function Defined as:

1. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
for age

2. serum glutamate pyruvate transaminase (SGPT) or ALT ≤ 135 U/L. For the purpose of
this study, the ULN for SGPT is 45 U/L.

- Adequate Cardiac Function Defined as: corrected QT interval (QTc) ≤ 480 msec

- Normal Creatinine Phosphokinase (CPK) Defined As Not Exceeding Maximum Value:

- Age: 0 to < 4 years; Male and female maximum CPK : 305 units/L

- 4 to < 7 years; Male and female maximum CPK : 230 units/L

- 7 to < 10 years; Male and female maximum CPK : 365 units/L

- 10 to < 12 years; Male maximum CPK: 215 units/L and female maximum CPK: 230 units/L

- 12 to < 14 years; Male maximum CPK: 330 units/L and female maximum CPK: 295 units/L

- 14 to < 16 years; Male maximum CPK: 335 units/L and female maximum CPK: 240 units/L

- 16 to < 19 years; Male maximum CPK: 370 units/L and female maximum CPK: 230 units/L

- ≥ 19 years; Male maximum CPK: 170 units/L and female maximum CPK: 145 units/L

- Willing to sign consent or assent/primary caregiver willing to give consent

Exclusion Criteria:

- Pregnancy or breast-feeding

- Concomitant medication dependency including corticosteroids, investigational drugs,
anti-cancer agents, anti-graft-versus-host disease (GVHD) agents post-transplant

- subjects who are unable to swallow a tablet or liquid must have a nasogastric (NG) or
gastric (G) tube through which the medicine can be administered

- subjects receiving known cytochrome P450 3A4 (CYP3A4) Inhibitors or Inducers

- subjects with uncontrolled infection

- subjects who received prior solid organ transplantation

- subjects with current or previous treatment with 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG CoA) reductase inhibitor (any statin)