Viral Therapy in Treating Patients With Metastatic Melanoma

Phase 2

Completed

Conditions: Stage IV Melanoma
Recurrent Melanoma

Interventions: Biological: wild-type reovirus

Registration Number: NCT00651157

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying the side effects and how well viral therapy works in treating patients with metastatic melanoma. Viral therapy may be able to kill tumor cells without damaging normal cells.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Histologically or cytologically confirmed malignant melanoma
- All melanomas, regardless of origin, are allowed
- Metastatic disease
Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20mm by conventional techniques or as ≥ 10 mm by spiral CT scan
Must have ≥ 1 metastatic lesion that can be safely biopsied
Must have received ≥ 1 prior treatment for metastatic disease
Not a candidate for curative surgery for metastatic disease
No known brain metastases
Eastern Cooperative Oncology Group performance status 0-2
Life expectancy > 12 weeks
Total White Blood Cell (WBC) ≥ 3,000/mcL
Absolute neutrophil count ≥ 1,500/mcL
Platelet count ≥ 100,000/mcL
Hemoglobin ≥ 9 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
Aspartate Aminotransferase (AST) ≤ 2.5 times ULN
Creatinine ≤ 1.5 times ULN
Troponin-T normal
Left ventricular ejection fraction (LVEF) ≥ 50% by ECHO or MUGA
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Agrees to provide blood and tissue samples for the mandatory translational research component of the study
Must be able to avoid direct contact with pregnant or nursing women, infants, and immuno compromised individuals during study and for ≥ 3 weeks following the last dose of study agent
No concurrent uncontrolled illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris, cardiac arrhythmia, or myocardial infarction within the past year
- Psychiatric illness/social situation that would preclude study compliance
No known HIV positivity
- Patients with a clinical history suggestive of an immuno compromised status are required to undergo HIV testing
More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas) and recovered
More than 2 weeks since prior radiotherapy, immunotherapy, or treatment with small molecule cell cycle inhibitors
No other concurrent investigational agents
No other concurrent anticancer therapy

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (viral therapy)	wild-type reovirus	Patients receive wild-type reovirus (Reolysin®) IV administered at a dose of 3 x 10\^10 TCID50/day in 250 mL 0.9% sodium chloride infused intravenously over 60 minutes daily on days 1-5 of each 28-day cycle. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Tumor Response	Every 4 weeks after 4 courses of treatment, assessed up to 5 years	A tumor response is defined to be a Complete Response (CR) or Partial Response (PR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the largest dimension (LD) of target lesions taking as reference the baseline sum LD.

Secondary Outcome Measures

Name	Time	Method
Time to Disease Progression	Time from registration to documentation of disease progression, assessed up to 5 years	Time to disease progression is defined as the time from registration to documentation of disease progression. If a patient dies without documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death.
Overall Survival	Time from registration to death due to any cause, assessed up to 5 years	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.