Dacarbazine and Recombinant Interferon Alfa-2b in Treating Patients With Primary Uveal Melanoma With Genetic Imbalance

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Recombinant interferon alfa-2b may interfere with the growth of tumor cells. Giving interferon alfa-2b together with dacarbazine may be an effective treatment for primary uveal melanoma. PURPOSE: This phase II trial is studying how well giving dacarbazine together with recombinant interferon alfa-2b works in treating patients with primary uveal melanoma with genetic imbalance.

Detailed Description
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PRIMARY OBJECTIVES: I. Assess disease-free survival (DFS) with sequential dacarbazine and interferon-alfa-2b as an adjuvant to primary therapy for patients with uveal melanoma with genetic imbalance. SECONDARY OBJECTIVES: I. Evaluate side effects and assess safety in the patient population. II. Examine the relationship between the levels of plasma biomarkers of immune function and tumor invasion and the clinical outcome. OUTLINE: Patients receive dacarbazine IV on days 1 and 29. Beginning 4 weeks after the second dose of dacarbazine, patients receive recombinant interferon alfa-2b subcutaneously 3 times a week for 24 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months.

Official Title
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Adjuvant Therapy for Patients With Primary Uveal Melanoma With Genetic Imbalance

Conditions
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Ciliary Body and Choroid Melanoma, Medium/Large Size, Ciliary Body and Choroid Melanoma, Small Size, Iris Melanoma, Recurrent Intraocular Melanoma

Intervention / Treatment
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* Biological: recombinant interferon alfa-2b
* Drug: dacarbazine
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Patients must have a diagnosis, either cytologic or histologic, of melanoma of the iris, ciliary body and/or choroid Patient's tumor must exhibit monosomy 3 and/or 8q amplification as determined by karyotype, comparative genomic hybridization (CGH), polymerase chain reaction (PCR)-based microsatellite, and/or Fluorescence in situ Hybridization (FISH) analysis; tissue or cells for analysis can be obtained at enucleation, resection, or by fine needle aspirate (FNA). Patients must have undergone adequate primary therapy; this can include enucleation, brachytherapy, proton beam radiotherapy, stereotactic irradiation, trans-scleral local resection, transretinal resection or diode laser thermotherapy Patients must have had chest X-ray and hepatic ultrasound or other imaging methods such as CT or MRI to eliminate distant disease Patients must have a performance status (ECOG) of < 2 Patients must be entered within 56 days of completing primary therapy White blood count (WBC) ≥ 3.0 x 10^9/L Neutrophils ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x upper limit of normal Hemoglobin ≥ 10 gm/100 ml Creatinine ≤ 2 mg/dl Bilirubin (total) ≤ 1.5 mg/dl Alanine transaminase (ALT) ≤ 1.5 x upper limit of normal Alkaline phosphatase ≤ 1.5 x upper limit of normal Aspartate aminotransferase (AST) ≤ 1.5 x upper limit of normal Patients must not have received any other systemic therapy for melanoma Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately All patients must be informed of the investigational nature of this study and must provide written informed consent in accordance with institutional and federal guidelines; a copy of the informed consent document signed by the patient must be given to the patient Exclusion Patients with metastasis Patients that are pregnant or breastfeeding Patients may not be receiving any other investigational agents Patients with a history of immunodeficiency or autoimmune diseases are not eligible; patients requiring therapy with corticosteroids or other immunosuppressives are not eligible; patients requiring ongoing replacement therapy with physiologic doses of corticosteroids will be eligible. Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements are not eligible Patients who are known to be positive for HIV or Hepatitis B Surface Antigen (HepBAg) No patient may have had a malignancy other than a malignant melanoma, with the following exceptions: basal or squamous cell carcinomas of the skin; carcinoma in-situ of the uterine cervix; any malignancy treated with curative intent and in complete remission for > 3 years Patients with organ allografts
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive dacarbazine IV on days 1 and 29. Beginning 4 weeks after the second dose of dacarbazine, patients receive recombinant interferon alfa-2b subcutaneously 3 times a week for 24 weeks in the absence of disease progression or unacceptable toxicity. | Biological: recombinant interferon alfa-2b<br>* Given subcutaneously (SC) 3 times a week for 24 weeks<br>* Other names: Intron A;Drug: dacarbazine<br>* Given IV on days 1 and 29<br>* Other names: DTIC-Dome;Other: laboratory biomarker analysis<br>* Correlative studies obtained prior to therapy, every 8 weeks while on therapy, and then every 6 months during follow-up<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Disease-free Survival (DFS) | DFS will be calculated from the date treatment starts to the date of documented recurrence or death. It will be summarized using the method of Kaplan and Meier. Treatment will be considered relatively ineffective in this population if the underlying 2-year DFS is <60%, whereas the combination will be considered promising if the underlying rate is >80%. | 5 years from time-of-enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicity or Grade 4 Adverse Events Via CTCAE Version 3.0 | Number of participants with toxicity as defined as an underlying risk of >33% Grade 3 (non blood/bone marrow) or Grade 4 adverse events that are related to therapy, assessed by NCI CTCAE version 3.0 | up to 32 weeks from start of study | 
| Changes in Plasma Biomarkers and Their Association With DFS | Plasma levels of these markers will be summarized at baseline and over time quantitatively and graphically. Specific regulators of immune escape and tumor cell invasion identified in uveal melanoma gene array studies will be measured. Peripheral blood cells and plasma will be analyzed for granulysin (a measure of natural killer cells (NK) activity), beta2-microglobulin, autotoxin, lysophosphatidic acid (a product of autotaxin), matrix metalloproteinase-7, tissue inhibitor of matrix metalloproteinase, and soluble E-cadherin. | 5 yrs from start of treatment |