Metastatic malignant melanoma remains a very difficult disease to treat. Previous phase II studies using biochemotherapy (combination of platinum-containing chemotherapy with IL-2 and IFNalpha) have shown response rates of about 50%. However, a site of frequent relapse is in the central nervous system (CNS). Temozolomide is an oral alkylating agent that has equivalent activity to dacarbazine, but it has the advantage of CNS penetration. We report the results of a phase II study using a novel biochemotherapy regimen containing temozolomide, cisplatin, decrescendo IL-2, IFNalpha, and GM-CSF in the treatment of stage IV melanoma. Seventy-one patients with histologically confirmed metastatic melanoma were enrolled between June 1998 and October 1999. Prior chemotherapy or IL-2 was not permitted. The median age was 54 years (range 22-72). Twenty-one patients (30%) had a history of treated brain metastases. Patients received temozolomide 150 mg/m2 orally days 1-5, cisplatin 30 mg/m2 IV days 1-3, IFNalpha 5 MU/m2 SQ on days 1-5, and IL-2 was administered in a decrescendo fashion according to the following schedule: day 1: 18 MU/m2 continuous IV infusion over 6 hours; day 2: 18 MU/m2 continuous IV infusion over 12 hours; day 3: 9 MU/m2 subcutaneously q12 hours; day 4: 4.5 MU/m2 subcutaneously x 1. Patients were also given GM-CSF 250 microg subcutaneously days 6-25. The cycles were repeated every 4 weeks. Partial responses were seen in 10 of the 71 patients (14%) with a median duration of response of 9.4 months. There were no complete responses. The median survival for all patients was 8.6 months. Further studies of this novel biochemotherapy regimen are not indicated. Other schedules that incorporate temozolomide and/or GM-CSF and further studies to define the optimal method of delivering IL-2 should be pursued.