Vakzination mit dendritischen Zellen im Vergleich zu DTIC – Ergebnisse einer Phase-III-Studie

Background: Progress in the treatment of patients with metastatic melanoma has been very limited over the last two decades. Vaccination with autologous dendritic cells (DC) was reported as being able to induce tumor regressions 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 no prior systemic chemotherapy were randomised to receive either chemotherapy with dacarbazine (DTIC) 850mg/m2 i.v. in 4-week intervals (arm A) or autologous peptide-pulsed DC in 2-week intervals for the first 5 vaccinations and every 4 weeks thereafter (arm B). DC were generated from peripheral blood monocytes by in-vitro culture using GM-CSF and IL-4 (d1-d5) followed by IL-1beta, IL-6, TNF-alpha, and PGE2 (d6). Matured DC were pulsed with different peptides derived from MAGE-1, MAGE-3, Melan-A, gp100, tyrosinase and influenza proteins depending on the patient's individual HLA-type (d6). The primary study endpoint was objective response to treatment (OR), secondary endpoints included safety, overall and progression-free survival. Patient recruitment was outlined as a total 190 patients evaluable for objective response. This sample size should enable the detection of an OR increase from 15% in the DTIC arm to 30% in the DC arm with a power of 80% and p below 0.05. Results: In the time period between 03/2000 and 07/2003 a total of 108 patients (intent-to-treat population, ITT, 55 DTIC, 53 DC) from 1 Swiss and 5 German centers were enrolled into the study. At the time of data analysis (09/2003) the objective response rates (CR+PR) were 5.5% in arm A and 3.8% in arm B, respectively (ITT). The median survival was 11.1 months in arm A and 9.0 months in arm B, respectively (ITT). There was no statistically significant difference for response, toxicity, overall and progression-free survival between both study arms. Accrual was halted prematurely because this first interim analysis indicated that an achievement of the study goals as defined in the protocol was highly improbable.