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Dacarbacine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) as first-line treatment of patients with metastatic melanoma: Results of a prospective-randomized phase III study.

7508 Background: Progress in the treatment of patients with metastatic melanoma has been very limited over the last two decades. Vaccination with autologous DC was reported as being able to induce some clinical regression in early clinical phase I/II studies.


METHODS
Patients with advanced metastatic melanoma, HLA-A1, -A2, -A3, -A24 or -B44 positivity, no brain or bone metastases and any previous systemic chemotherapy were randomised to receive DTIC (850 mg/m2 d1, every 28 days with 4-week intervals (arm A) or intradermal vaccination with autologous peptide-pulsed dendritic cells in 2-week intervals for the first 5 vaccinations and every 4 weeks thereafter (arm B). DC were generated from peripheral blood after leukapheresis and culturing monocytes in-vitro in GM-CSF, IL-4 (d1-d5) and a maturing cytokine cocktail (IL-1β, IL-6, TNFα and PGE2) on day 6. Matured DC were pulsed subsequently with peptides derived from MAGE-1, MAGE-3, Melan-A, gp100, tyrosinase and influenza proteins as a control depending on the individual HLA-type (d6). Primary study endpoint was objective response to treatment (OR), secondary endpoints included safety, overall and progression-free survival. The planned accrual per arm was set at 119 patients under the basic assumption that the response rate would double from 15 % for treatment with DTIC to 30 % for DC-vaccination to reach significance at 0.05 with 80% power.


RESULTS
In the time period between 1/2001 and 6/2003 a total of 108 (intention-to-treat population, ITT; 55 DTIC, 53 DC) patients were randomized from 1 Swiss and 5 German centers with experience in DC generation and therapy. Accrual was halted prematurely by the data monitoring board because data indicated that the study goals could not be achieved. OR (CR+PR) were 5.5% in arm A and 3.8% in arm B, respectively (ITT). There was no statistically significant difference for response, toxicity, overall and progression-free survival between both study arms. Subset analysis indicated a trend for benefical effect of HLA-A2 and a disadvantage for HLA-B44.


CONCLUSION
DC-based vaccination is as poorly active as standard DTIC chemotherapy in metastatic melanoma. Whether further selection of patients and improved DC generation protocols will lead to a statistical benefit remains topic of further studies. [Table: see text].