Vaccine Therapy in Treating Patients With Stage IV Cutaneous Melanoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Vaccines made from a person's dendritic cells and antigens may make the body build an immune response to kill tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of vaccine therapy using autologous dendritic cells with antigens in treating patients who have stage IV cutaneous melanoma.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the safety and tolerability of vaccination with autologous monocyte-derived dendritic cells (DC) transfected with RNAs encoding Melan-A, MAGE-3, and survivin antigens in patients with stage IV cutaneous melanoma. Determine whether tumor antigen-specific T-cell responses are induced in patients treated with this vaccine. Determine whether simultaneous loading of DC with keyhole limpet hemocyanin (KLH) significantly enhances induction of the Melan-A, MAGE-3, and survivin antigens in these patients. Secondary Determine clinical antitumor activity (e.g., objective tumor response, time to tumor progression, progression-free interval, and overall survival) in patients treated with this vaccine. OUTLINE: This is an open-label, nonrandomized study. Phase I: Beginning 9-11 days before vaccination, patients undergo leukapheresis for collection of peripheral blood mononuclear cells (PBMCs). PBMCs are processed for the generation of dendritic cells (DC) to be used for vaccinations. PBMCs are transfected with RNAs encoding for Melan-A, MAGE-3, and survivin antigens. DC are pulsed with keyhole limpet hemocyanin (KLH) for some patients. Patients receive antigen-pulsed (with or without KLH) DC vaccination subcutaneously (SC) on days 1, 15, 43, and 71 in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may proceed to the phase II portion of the study. Phase II: Patients undergo leukapheresis as in phase I on days 102, 354, and 690. Patients receive up to 6 additional booster vaccinations SC as in phase I on days 127, 185, 269, 356, 521, and 692. Patients are followed for 10 years. PROJECTED ACCRUAL: A total of 8-30 patients will be accrued for this study within 6-12 months.

Official Title
-----------------
Vaccination of Stage IV Cutaneous Melanoma Patients With Mature, Autologous Monocyte-Derived Dendritic Cells Transfected With RNAs Encoding for Mage-3, MelanA, and Survivin Antigens

Conditions
-----------------
Melanoma (Skin)

Intervention / Treatment
-----------------
* Biological: Autologous Dendritic Cells loaded with MAGE-A3, MelanA and Survivin


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed cutaneous* melanoma Stage IV Incurable by surgical resection Progressive disease after at least 1 standard chemotherapy or chemoimmunotherapy regimen (e.g., dacarbazine or cisplatin monotherapy) Unidimensionally or bidimensionally measurable disease by physical examination (e.g., cutaneous metastases) and/or noninvasive radiological procedures No active CNS metastases by CT scan or MRI Previously treated (e.g., excision of a single metastasis) CNS metastases are allowed provided there are no signs of active CNS metastases NOTE: *Metastatic melanoma with unidentified primary tumor allowed provided an ocular melanoma can be definitely excluded and origin from the skin is likely PATIENT CHARACTERISTICS: Age 18 and over Performance status Karnofsky 60-100% Life expectancy At least 4 months Hematopoietic WBC greater than 2,500/mm^3 Neutrophil count greater than 1,000/mm^3 Lymphocyte count greater than 700/mm^3 Platelet count greater than 75,000/mm^3 Hemoglobin greater than 9 g/dL No bleeding disorder Hepatic Bilirubin less than 2.0 mg/dL No evidence of hepatitis B or C infection Renal Creatinine less than 2.5 mg/dL Cardiovascular No clinically significant heart disease Pulmonary No respiratory disease Immunologic HIV-1 and HIV-2 negative HTLV-1 negative No active systemic infection No immunodeficiency disease No active autoimmune disease (e.g., lupus erythematosus, autoimmune thyroiditis or uveitis, multiple sclerosis, or inflammatory bowel disease) Vitiligo allowed Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 4 weeks after study participation Stable medical condition No other major serious illness No contraindication to leukapheresis No organic brain syndrome or significant psychiatric abnormality that would preclude study participation or follow-up No other active malignant neoplasm PRIOR CONCURRENT THERAPY: Biologic therapy More than 4 weeks since prior immunotherapy No other concurrent immunotherapy during and for 2 weeks after study participation Chemotherapy More than 4 weeks since prior systemic chemotherapy (6 weeks for nitrosoureas [e.g., fotemustine]) No concurrent chemotherapy during and for 2 weeks after study participation Endocrine therapy No concurrent corticosteroids during and for 2 weeks after study participation Radiotherapy More than 2 weeks since prior radiotherapy No prior radiotherapy to the spleen Concurrent palliative radiotherapy to selected metastases (e.g., due to pain or local complications such as compression) is allowed Surgery Recovered from prior surgery No prior splenectomy No prior organ allografts Concurrent surgical therapy to selected metastases (e.g., due to pain or local complications such as compression) is allowed Selected accessible metastases may be removed for tumor infiltrating lymphocyte assay or other immunomonitoring investigations (e.g., expression of tumor antigens and HLA molecules) Other No other concurrent investigational drug or paramedical substance during and for 2 weeks after study participation No concurrent participation in another clinical trial Concurrent palliative medication allowed (e.g., acetaminophen, indomethacin, or opiates)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Autologous Dendritic Cells loaded with MAGE-A3, MelanA and Survivin|Within cohort 1 patients received the vaccine intradermally; in cohort 2 the route of Administration was intravenous Infusion, half of the patients had additional loading with RNA coding for EL-Selektin; in cohort 3 the vaccines was again infused intravenously, the cells were matured not with MCM.mimic as in cohort 1 and 2 but either with TriMix or MCM-mimic plus CD40L-RNA.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability at every visit |  | 3 months | 
| Overall survival as assessed by clinical staging (CT scan, positron emission tomography [PET]) every 3 months |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression as assessed by clinical staging (CT scan, PET) every 3 months |  | 3 months | 
| Objective tumor response as assessed by clinical staging (CT scan, PET) every 3 months |  | 3 months | 
| Duration of response as assessed by clinical staging (CT scan, PET) every 3 months |  | 3 months | 
| Induction of antigen-specific immune responses as assessed by elispot and tetramer staining at every visit |  | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV melanoma, recurrent melanoma