Viral Therapy in Treating Young Patients With Relapsed or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of
REOLYSIN administered as an intravenous infusion daily for 5 days, every 28 days to children
with relapsed or refractory solid tumors.

II. To define and describe the toxicities of Reolysin in these patients. III. To define the
toxicity and tolerability of combining Reolysin with oral cyclophosphamide in these
patients.

IV. To characterize the pharmacokinetics (time course of viral clearance) of Reolysin in
children with refractory cancer.

SECONDARY OBJECTIVES:

I. To define the antitumor activity of Reolysin within the confines of a phase I study.

II. To evaluate the development of neutralizing antibodies to Reolysin following intravenous
administration of Reolysin alone and in combination with cyclophosphamide.

III. To assess the biologic activity of Reolysin.

OUTLINE: This is a dose-escalation study of wild-type reovirus.

Patients receive wild-type reovirus intravenously (IV) over 60 minutes once daily (QD) on
days 1-5. Some patients also receive cyclophosphamide orally (PO) on days 1-21. Treatment
repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 1 year.

Inclusion Criteria:

- Patients with relapsed or refractory solid tumors, with the exception of central
nervous system (CNS) tumors and lymphomas, are eligible; patients must have had
histologic verification of malignancy at original diagnosis or relapse

- Patients must have either measurable or evaluable disease

- Patient's current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life

- Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age; patients who are unable to walk because of paralysis, but who are up in
a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

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

- Must not have received myelosuppressive chemotherapy within 3 weeks of enrollment
onto this study (6 weeks if prior nitrosourea)

- At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta)
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

- 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

- At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor
vaccines

- At least 3 half-lives of the antibody after the last dose of a monoclonal antibody

- >= 2 weeks for local palliative radiation therapy (XRT) (small port); >= 24 weeks
must have elapsed if prior total-body irradiation (TBI), craniospinal XRT or if >=
50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone
marrow (BM) radiation

- No evidence of active graft vs host disease and >= 12 weeks must have elapsed since
stem cell transplant or infusion

- Patients must not have received any previous viral-based anti-neoplastic therapies

- Viral immunizations, including influenza, may not have been administered within 7
days prior to enrollment; Note: patients may not receive any viral immunizations
after enrolling on study until 28 days post their last planned REOLYSIN infusion

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 100,000/mm^3 (transfusion independent (transfusion independent,
defined as not receiving platelet transfusions within a 7 day period prior to
enrollment)

- Patients with known bone marrow metastatic disease will be eligible for study but not
evaluable for hematologic toxicity (maximum of one per cohort); such patients must
meet the blood counts above (may receive transfusions provided they are not be known
to be refractory to red cell or platelet transfusion); if dose-limiting hematologic
toxicity is observed, all subsequent patients enrolled must be evaluable for
hematologic toxicity

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR
serum creatinine based on age and/or gender as follows:

- 0.8 mg/dL (3 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)

- Bilirubin (sum of conjugated plus unconjugated) =< 1.5 x upper limit of normal (ULN)
for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Serum albumin >= 2 g/dL

- Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by gated
radionuclide study

- Normal pulmonary function tests (PFTs) (including diffusion capacity of carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen); for patients who do not have
respiratory symptoms, full PFTs are NOT required

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled

- Nervous system disorders National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events version 4 (CTCAE v. 4) resulting from prior therapy must be =<
grade 2

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method

- Patients who have an uncontrolled infection are not eligible

- Patients with chronic diarrhea, urinary incontinence during the day or at night, or
patients who are not completely toilet trained will not be eligible

- Patients will be excluded if they have household contacts who are pregnant,
immunosuppressed or infants less than 3 months of age; household contacts are defined
as anyone living with the patient during the isolation period of the treatment cycles

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible

- Patients with known human immunodeficiency virus (HIV) or hepatitis B or C are
excluded due to risk of viral infectivity of REOLYSIN; therefore, patients with a
pre-existent infection are not eligible

- Patients who are currently receiving other anti-cancer agents are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection post
transplant are not eligible for this trial

- Patients must not have received corticosteroids, immune modulators or antiviral
therapy for 7 days prior to enrollment and must not have an anticipated need for any
of these therapies, intravenous immune globulin (IVIG) must not have been
administered within 2 weeks prior to enrollment

- Patients should avoid taking acetaminophen with REOLYSIN; whenever suitable,
physicians should utilize alternative medications

- Patients with known germline mutations affecting Ras activation (e.g. NF-1,
Cardio-facial-cutaneous syndrome, Noonan syndrome, Costello syndrome) will be
excluded from enrollment

- Patients with known metastatic CNS disease involvement are excluded

- Patients with primary CNS tumors are excluded