Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study.

Abstract

Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain barrier, in combination with interferon alpha-2b (IFN-alpha2b). Twenty-three patients with MM were enrolled in this single-center, open-label study. Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received oral TMZ (200 mg/m(2) per day) for 5 days every 28-day cycle plus subcutaneous IFN-alpha2b (5 million International Units [MIU]/m(2) per day, 3 times per week). A second cohort (n = 17 patients) received TMZ 150 mg/m(2) per day on the same schedule plus escalating doses of IFN-alpha2b (5.0 MIU/m(2) per day, 7.5 MIU/m(2) per day, and 10 MIU/m(2) per day 3 times per week). The most common adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most toxicity was mild to moderate in severity. The primary dose-limiting toxicity was thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m(2) plus IFN-alpha2b 7.5 MIU/m(2) or TMZ 200 mg/m(2) plus IFN-alpha2b 5.0 MIU/m(2). Four patients (17%) had objective responses (one complete response and three partial responses), and four patients had stable disease. The median survival was 9 months. The pharmacokinetics of TMZ were not affected by coadministration of IFN-alpha2b. TMZ can be combined safely with IFN-alpha2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases.