Recurrent Melanoma, Stage IV Melanoma
Conditions
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.
Interventions
BIOLOGICALwild-type reovirus
Given 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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Twenty three participants were enrolled onto this study between August 2008 and January 2010.
Pre-assignment details
One participant died prior to receiving any treatment and is not included in this study summary. One participant was found to be ineligible and was not used in the analysis of any endpoint, but was used for reporting toxicity. Therefore, 21 participants were used for the primary analysis and 22 participants are used to report toxicity.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Viral Therapy) 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. | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Treatment (Viral Therapy) |
|---|---|
| Age, Continuous | 65 years |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 11 / 22 |
Outcome results
Primary
Tumor Response
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.
Time frame: Every 4 weeks after 4 courses of treatment, assessed up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Viral Therapy) | Tumor Response | Complete Response (CR) | 0 participants |
| Treatment (Viral Therapy) | Tumor Response | Partial Response (PR) | 0 participants |
Secondary
Overall Survival
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.
Time frame: Time from registration to death due to any cause, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Viral Therapy) | Overall Survival | 5.42 months |
Secondary
Time to Disease Progression
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.
Time frame: Time from registration to documentation of disease progression, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Viral Therapy) | Time to Disease Progression | 45 days |