Seneca Valley Virus-001 and Cyclophosphamide in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features

OBJECTIVES:

Primary

- To estimate the maximum-tolerated dose and/or recommended phase II dose of Seneca
Valley virus-001 (NTX-010) when administered as a single infusion to pediatric patients
with relapsed or refractory neuroblastoma, rhabdomyosarcoma, or rare tumors with
neuroendocrine features (Wilms tumor, retinoblastoma, adrenocortical carcinoma, or
carcinoid tumors). (Part A [completed])

- To confirm that there is viral replication in these patients following NTX-010
administration. (Part A [completed])

- To define and describe the toxicities of NTX-010 when administered on this schedule.
(Part A [completed])

- To determine whether the number of regulatory T cells (as measured by flow cytometry)
can effectively be reduced following administration of NTX-010 plus low-dose metronomic
and intravenous cyclophosphamide. (Part B)

- To characterize the pharmacokinetics (time course of viral clearance) following NTX-010
administration in these patients.

Secondary

- To preliminarily define the antitumor activity of NTX-010 within the confines of a
phase I study. (Part A [completed])

- To evaluate the development of neutralizing antibodies to NTX-010 following IV
administration of NTX-010. (Part A [completed])

- To evaluate development of neutralizing antibodies to NTX-010 following the combination
of NTX-010 and cyclophosphamide. (Part B)

- To investigate the presence and permissivity of occult circulating tumor cells prior to
and after the initial intravenous administration of NTX-010.

OUTLINE: This is a multicenter study.

Part A (completed): Patients receive Seneca Valley virus-001 (NTX-010) IV over 1 hour on day
1.

Part B: Patients receive cyclophosphamide IV orally (PO) on days 1-14 and NTX-010 IV over 1
hour on day 8. In the absence of disease progression or unacceptable toxicity, patients then
receive cyclophosphamide orally (PO) on days 22-35, plus cyclophosphamide IV over 1 hour and
NTX-010 IV over 1 hour on day 29.

Tumor tissue samples are collected at baseline for biomarker studies. Blood and stool
samples are collected periodically for neutralizing antibody and viral clearance studies.
Additional blood samples may also be collected for the presence and permissivity of occult
tumor cells.

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

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of 1 of the following:

- Neuroblastoma

- Rhabdomyosarcoma

- Wilms tumor

- Retinoblastoma

- Adrenocortical carcinoma

- Carcinoid tumor

- Relapsed or refractory disease

- Measurable or evaluable disease

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life

- No known pulmonary tumors or metastases > 5 cm, as evaluated by chest CT scan

- No clinically significant pulmonary and/or pericardial effusions (≥ grade 3), as
evaluated by ECHO

- No primary CNS tumors or known metastatic CNS disease involvement

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (for patients > 16 years of age)

- Lansky PS 50-100% (for patients ≤ 16 years of age)

- Peripheral ANC ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as no platelet
transfusions within a 7-day period before study enrollment)

- Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)

- Creatine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on
age/gender as follows:

- ≤ 0.8 mg/dL (for patients 3 to 5 years of age)

- ≤ 1.0 mg/dL (for patients 6 to 9 years of age)

- ≤ 1.2 mg/dL (for patients 10 to 12 years of age)

- ≤ 1.4 mg/dL (for female patients ≥ 13 years of age)

- ≤ 1.5 mg/dL (for male patients 13 to 15 years of age)

- ≤ 1.7 mg/dL (for male patients ≥ 16 years of age)

- Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal
(ULN)

- SGPT ≤ 110 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)

- Serum albumin ≥ 2 g/dL

- Oxygen saturation > 92% on room air

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to comply with the safety monitoring requirements of the study, in the opinion
of the investigator

- Completely toilet trained

- No chronic diarrhea or urinary incontinence during the day or night, , and no
in-dwellling urinary catheters

- No uncontrolled infection

- No known pregnant member of the household

PRIOR CONCURRENT THERAPY:

- Fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

- At least 6 months since prior total-body irradiation (TBI), craniospinal
radiotherapy, or radiotherapy to ≥ 50% of the pelvis

- At least 3 months since prior stem cell transplantation or rescue (without TBI)

- No evidence of active graft-vs-host disease

- At least 6 weeks since other prior substantial bone marrow radiotherapy or treatment
with therapeutic doses of MIBG

- More than 3 weeks since prior myelosuppressive chemotherapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- More than 7 days since prior growth factor(s) that support platelet or white blood
cell number or function

- At least 7 days since prior biologic agents

- At least 3 half-lives since prior monoclonal antibodies

- More than 7 days since prior viral immunizations, including influenza

- At least 42 days since the completion of any type of immunotherapy, e.g., tumor
vaccines

- No other viral immunizations after enrolling on study until 28 days after their last
planned Seneca Valley virus-001 infusion or until documented viral clearance,
whichever is longest

- Concurrent corticosteroids allowed provided the patient has been on a stable or
decreasing dose for the past 7 days

- No other concurrent investigational drugs

- No other concurrent anticancer agents (e.g., chemotherapy, radiotherapy,
immunotherapy, or biologic therapy)

- Prior treatment with Seneca Valley virus-001 is not allowed