GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma

Summary Background: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy. Patients and methods: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m 2 days 1-3), dacarbazine (220 mg/m 2 days 1-3), interleukin-2 (9 MIU/m 2 / 24h) and interferon-a2b (5 MIU/m 2 ) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 ug/m 2 days 4-5 and 15-16; 2) as 1) plus 225 ug/m 2 days 6-10 and 17-21; 3) 450 ug/m 2 days 4-10 and 15-21. Each cycle was 28 days. Results: Constitutional side effects were the major nonhaematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-a. Conclusions. The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.