The purpose of this study is to assess intranodal immunotherapy in locally advanced to metastatic melanoma patients (American Joint Committee on Cancer [AJCC] stages IIb to IV).

For this, the investigators capitalize on their previous melanoma clinical trial (published by Zajac P et al in Human Gene Ther 2003) and take advantage of a proprietary recombinant vaccinia virus (replication inactivated) expressing 5 minigenes: 3 melanoma associated antigens and 2 costimulatory molecules. Immunization with the recombinant vaccinia virus is followed by 3 boosts with soluble, synthetic melanoma associated antigens.

The patients are immunized intranodally (groin lymph node) under ultrasonographic guidance in an outpatient clinic. The protocol foresees 2 cycles of immunotherapy for alternate weeks and lasts 15 weeks.

Condition	Intervention	Phase
Melanoma	Gene Transfer: Intranodal immunization with a recombinant vaccinia virus expressing 5 transgenes  Vaccine: Intranodal booster immunizations with synthetic melanoma associated epitopes	Phase I Phase II

Further Study Details: 

Primary Outcomes: Safety evaluation; Clinical response; Immune response assessment
Secondary Outcomes: Survival (disease-free survival [DFS], overall survival [OS]); Dose adaptation
Expected Total Enrollment:  20

The investigators have conducted a phase I/II clinical trial based on the intradermal administration to stage III/IV melanoma patients of a recombinant vaccinia virus encoding tumor associated antigens and costimulatory epitopes for the priming of immune responses, followed by boosts with corresponding synthetic peptides (Zajac P et al in Human Gene Ther 2003). Specific cytotoxic T cells could be induced in a majority of patients following priming, but sustained responsiveness could not be maintained by peptide boosting on a long term basis. Emerging evidence supports the notion that expansion of specific T cells requires trafficking of antigen presenting cells loaded with specific determinants to lymphatic nodes, as induced, among others, by pro-inflammatory stimuli. Therefore, we now adopt the intranodal injection of the immunogenic formulations. As for the former melanoma active specific immunotherapy trial, GM-CSF is used as a supporting cytokine. The epitopes considered are expressed, either all or some of them, in over 90% of the melanomas in Western countries; namely, we immunize with Mart-1/Melan-A epitope 27-35, Gp-100 epitope 280-288 and tyrosinase epitope 1-9. As a consequence, HLA-A2 positivity is mandatory for inclusion in the trial. The 2 costimulatory molecules expressed by cells infected with our replication-incompetent recombinant vaccinia virus are B7.1 (CD80) and B7.2 (CD86).

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Patients older than 18 years
• Histologically proven melanoma in AJCC stages IIb to IV
• Resected, recurrent or disseminated disease
• HLA-A2.1 MHC phenotype
• Karnofsky performance status equal or higher than 70%

Exclusion Criteria:

• Patients younger than 18 years
• Pregnancy or inability to perform anticonception
• MHC phenotype other than HLA-A2.1
• Other concurrent malignant disease
• Estimated life expectancy of less than 6 months
• Allergic skin diseases, including eczema, psoriasis and neurodermitis
• Fever or active infection of the respiratory system
• Concurrent severe cardiac or pulmonary disease (New York Heart Association [NYHA] III and IV)
• Significant impairment of liver or kidney function (bilirubin > 30umol/l, GOT >2.5xN, GPT >2.5xN, alkaline phosphatase >2.5xN, creatinine >1.5xN adapted to the age)
• Impairment of the immune system (leucocyte counts <3000/mm3 or granulocytes counts <1500/mm3)
• Concurrent immunosuppressive therapy
• Preexisting severe anemia (hemoglobin lower than 80 g/l)
• Preexisting thrombocytopenia (platelet counts lower than 75,000/ul)
• Ongoing chemotherapy or chemotherapy completed less than 6 weeks before enrollment in the trial
• Any medical or psychiatric condition which, in the opinion of the treating physician or principal investigator, would unacceptably reduce the safety of the proposed treatment, would impair the delivery of treatment, or would preclude obtaining voluntary informed consent
• Patients receiving any other concurrent investigational treatment, or any other concurrent treatment for their cancer
• Patients who cannot avoid close contact with children less than 3 years of age or with immunocompromised household members

Please refer to this study by ClinicalTrials.gov identifier  NCT00116597

Michel Adamina, M.D.      +41 61 265 25 25    madamina@uhbs.ch

Switzerland
      University Hospital Basel, Basel,  4031,  Switzerland; Recruiting

Study chairs or principal investigators

Michel Adamina, M.D.,  Principal Investigator,  University Hospital Basel   
Daniel Oertli, M.D.,  Study Chair,  University Hospital Basel   
Michael Heberer, M.D.,  Study Director,  University Hospital Basel   
Giulio C Spagnoli, M.D.,  Principal Investigator,  University Hospital Basel   
Walter R Marti, M.D.,  Principal Investigator,  University Hospital Basel   

Study ID Numbers:  GT1999017/05.050; SNF grant NPF 37, 4037-55151; SNF grant 31-57473.99
Record last reviewed:  June 2005
Last Updated:  June 30, 2005
Record first received:  June 29, 2005
ClinicalTrials.gov Identifier:  NCT00116597
Health Authority: Switzerland: Swissmedic
ClinicalTrials.gov processed this record on 2005-07-05