Abstract
BACKGROUND
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 α‐2b (IFN‐α2b).
METHODS
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‐α2b (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‐α2b (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).
RESULTS
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‐α2b 7.5 MIU/m^2^ or TMZ 200 mg/m^2^ plus IFN‐α2b 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‐α2b.
CONCLUSIONS
TMZ can be combined safely with IFN‐α2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases. Cancer 2003;97:121–7. © 2003 American Cancer Society.
DOI 10.1002/cncr.11041