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

• Maximum-tolerated dose (MTD) and/or recommended phase II dose of wild-type reovirus (Reolysin) [ Designated as safety issue: Yes ]
• Adverse events of Reolysin alone and in combination with oral cyclophosphamide as assessed by NCI CTCAE v. 4.0 [ Designated as safety issue: Yes ]

• Pharmacokinetics (time course of viral clearance) of Reolysin [ Designated as safety issue: No ]
• Antitumor activity of Reolysin [ Designated as safety issue: No ]
• Development of neutralizing antibodies to Reolysin [ Designated as safety issue: No ]

This phase I trial is studying the side effects and the best dose of viral therapy in treating young patients with relapsed or refractory solid tumors. A virus called wild-type reovirus, which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving wild-type reovirus together with cyclophosphamide may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To estimate the maximum-tolerated dose (MTD) and/or recommended phase II dose of wild-type reovirus (Reolysin) in 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 (Reolysin).

Patients receive Reolysin IV over 60 minutes once daily on days 1-5. Some patients also receive oral cyclophosphamide 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.

• Biological: wild-type reovirus
  Given IV
  Other Name: REOLYSIN
• Other: pharmacogenomic studies
  Correlative studies
  Other Name: Pharmacogenomic Study
• Drug: cyclophosphamide
  Given orally
  Other Names:

  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
• Other: laboratory biomarker analysis
  Correlative studies

Inclusion Criteria:

• Diagnosis of relapsed or refractory solid tumors

  • Must have had histologic verification of malignancy at original diagnosis or relapse
  • Disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • No primary central nervous system (CNS) tumors or lymphomas
• Measurable or evaluable disease
• No known germline mutations affecting Ras activation (e.g., cardio-facial-cutaneous syndrome, Noonan syndrome, Costello syndrome)
• No known metastatic CNS disease
• Karnofsky performance status (PS) 50-100% for patients > 16 years of age OR Lansky PS 50-100% for patients ≤ 16 years of age
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count ≥ 100,000/mm³ (transfusion independent, defined as ≥ 7 days since platelet transfusion prior to enrollment)

• 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 + unconjugated) ≤ 1.5 times upper limit of normal (ULN)
• Alanine aminotransferase (ALT) =< 110 U/L (ULN for ALT is 45 U/L)
• Serum albumin ≥ 2 g/dL
• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by gated radionuclide study

• Pulmonary function tests (PFTs), including diffusion capacity of carbon monoxide (DLCO), normal for patients with respiratory symptoms (e.g., dyspnea at rest, known requirement for supplemental oxygen)

  • Full PFTs not required for patients without respiratory symptoms
• Seizure disorder allowed provided it is well controlled with anticonvulsants
• Nervous system disorders (NCI CTCAE v. 4) resulting from prior therapy must be ≤ grade 2
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No uncontrolled infections
• No chronic diarrhea, urinary incontinence during the day or at night, or patients who are not completely toilet trained
• No household contacts (living with patient during the 4 weeks of treatment) who are pregnant, immunosuppressed, or infants < 3 months of age
• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• No known HIV infection, hepatitis B or C, or any pre-existing infection
• Recovered from acute toxic effects of all prior anti-cancer chemotherapy and immunizations
• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)
• At least 14 days since prior long-acting growth factor (e.g., Neulasta) or ≥ 7 days since short-acting growth factor
• At least 7 days since prior biologic agent (anti-neoplastic agent)
• At least 16 weeks since prior immunotherapy (e.g., tumor vaccines)
• At least 3 half-lives since prior monoclonal antibody

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

  • At least 24 weeks since prior total body irradiation, craniospinal radiotherapy, or ≥ 50% of radiotherapy to the pelvis
  • At least 6 weeks since other prior substantial bone marrow radiation
• At least 12 weeks since prior stem cell transplant or infusion with no evidence of active graft-vs-host disease

• More than 7 days since prior viral immunizations, including influenza vaccine

  • Patients may not receive any viral immunizations after enrolling on study and for ≥ 28 days after their last planned Reolysin infusion

• More than 7 days since prior corticosteroids, immune modulators, or antiviral therapy

  • Intravenous immune globulin (IVIG) may not be given within 2 weeks of Reolysin administration
• No prior viral-based anti-neoplastic therapies
• No other concurrent investigational drugs
• No other concurrent anticancer agents including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
• No concurrent cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease after bone marrow transplant or organ rejection after transplant
• No concurrent corticosteroids (with the exception of hydrocortisone as a treatment for anaphylaxis), immune modulators, antiviral therapy, or IVIG
• No concurrent acetaminophen