Viral Therapy in Treating Patients With Metastatic Melanoma

• Clinical benefit rate [ Time Frame: Every 4 weeks during treatment, every 6 months for 2 years after treatment and then annually assessed up to 5 years ] [ Designated as safety issue: No ]
  Clinical benefit rate defined as the number of patients who remain on study treatment and whose disease either meets the Response Evaluation Criteria in Solid Tumors (RECIST) criteria for complete response [CR] or partial response [PR] on two consecutive evaluations at least 4 weeks apart or meets the RECIST criteria for STABLE disease at least 8 weeks post-registration divided by the number of patients who met the eligibility criteria, signed a consent form and begun treatment.
  
  
• Tumor response rate [ Time Frame: Every 4 weeks after 4 courses of treatment, assessed up to 5 years ] [ Designated as safety issue: No ]
  A tumor response is defined to be a CR or PR as defined by the RECISTcriteria noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. The tumor response rate will be estimated by the number of patients whose disease meets the RECIST criteria for CR or PR on two consecutive evaluations at least 4 weeks apart divided by the total number of eligible patients who initiated treatment times 100%. A 90% two-sided confidence interval for the true tumor response rate will be constructed using the Duffy and Santner approach.
  
  

• Survival time [ Time Frame: Time from registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
  
• Time to disease progression [ Time Frame: Time from registration to documentation of disease progression, assessed up to 5 years ] [ Designated as safety issue: No ]
  Sites of progression will be noted. Time to event distributions will be estimated using the Kaplan-Meier method.
  
  
• Toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Weekly during course , prior to subsequent treatment courses, and up to 5 years after completion of treatment ] [ Designated as safety issue: Yes ]
  A plot of viral replication 1 week post treatment versus development of a severe toxicity after the first cycle of treatment (yes/no) will be constructed to visually assess whether viral replication differs with respect to development of severe toxicity.
  
  
• Immunologic parameters [ Time Frame: At baseline, every other month for 1 year, and at 6 and 12 months after completion of treatment ] [ Designated as safety issue: No ]
  For each of the immunologic parameters, a times series plot will be constructed. A grid reflecting the percent change from pretreatment levels will be constructed. This grid can be inspected to see if the changes seen in a given immunologic parameter differ between patients who derive clinical benefit and patients who do not derive clinical benefit.
  
  
• Viral replication in metastatic melanoma deposits [ Time Frame: At 1 week (7 days) after treatment initiation ] [ Designated as safety issue: No ]
  A plot of viral replication 1 week post treatment versus clinical benefit (yes/no) will be constructed to visually assess whether viral replication differs between those who derive clinical benefit and those who do not derive clinical benefit. A plot of viral replication 1 week post treatment versus development of a severe toxicity after the first cycle of treatment (yes/no) will be constructed to visually assess whether viral replication differs with respect to development of severe toxicity.
  
  
• p38 expression in pretreatment tumor specimens [ Time Frame: At baseline ] [ Designated as safety issue: No ]
  Point and interval estimates of the true proportion of patients with p38 positive disease who derive clinical benefit as well as point and interval estimates of the true proportion of patients with p38 negative disease who derive clinical benefit will be constructed using the properties of the binomial distribution.
  
  
• Fludeoxyglucose (FDG) uptake [ Time Frame: At baseline and at 4 weeks after treatment initiation ] [ Designated as safety issue: No ]
  A times series plot of FDG uptake will be constructed. This plot will be visually assessed for trends. A 95% confidence interval for the proportion of patients who have at least a 50% reduction from pre-treatment FDG uptake levels at 4 weeks post treatment initiation will be constructed using the properties of the binomial distribution.
  
  

PRIMARY OBJECTIVES:

I. Assess the antitumor effect of wild-type reovirus (Reolysin®), in terms of tumor response rate and clinical benefit rate (i.e., partial response and complete response), in patients with metastatic melanoma.

II. Assess the toxicity profile of Reolysin® in these patients.

SECONDARY OBJECTIVES:

I. Assess the progression-free survival and overall survival of these patients. II. Assess viral replication in metastatic melanoma deposits after intravenous administration of Reolysin®.

III. Assess the impact of pre-existing anti-reoviral immunity (as represented by p38 expression in pretreatment tumor specimens) on the efficacy and toxicity of Reolysin®.

IV. To measure the effect of Reolysin® on the immune system, in terms of dendritic cell activation, T-cell activation, presence of Treg cells in tumor specimens, and the frequency of T cells, B cells, NK cells, and peptide specific cytotoxic T lymphocytes reactive against melanoma differentiation antigen peptides (gp100, MART-1, and tyrosinase).

V. To assess the induction of melanoma specific immune response, in terms of the presence of melanoma differentiation antigens (gp100, MART-1, and tyrosinase) in tumor specimens.

OUTLINE: This is a multicenter study.

Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo tumor tissue samples collection at baseline and at 1 week after initiation of treatment for correlative laboratory studies. Tissue samples are analyzed for p38/MAPK activation status by IHC; reoviral replication in metastatic deposits by electron microscopy; and immunologic parameters by IHC. Blood samples are collected at baseline and periodically during the study. Blood samples are analyzed for immunologic parameters by tetramer and ELISPOT technology and for neutralizing antibodies against reovirus.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for up to 5 years.