A phase II study of thalidomide and temozolomide in patients with brain metastases from malignant melanoma: lymphopenia correlates with response

BACKGROUND Central nervous system (CNS) metastases develop in nearly half of patients with advanced melanoma and in 15-20% CNS is the first site of relapse. Median overall survival is short, ranging from two to four months, and one-year survival rate is only 10-15%. THA has been shown to have both anti-angiogenetic and immuno-modulating effects. TMZ is an oral alkylating agent with an excellent oral bioavailability and it is highly lipophillic with an ability to penetrate the blood-brain barrier. TMZ and THA in combination were tested in patients with brain metastases from malignant melanoma. METHODS Between June 2004 and February 2007 patients with measurable metastatic melanoma in progression and PS ≤ 1 received TMZ in a dose of 150 mg/m(2) qd for seven days, followed by seven days off therapy and THA in 200 mg qd, both orally administered. Concomitant treatment with steroids was allowed. PBMCs were collected from the last 14 consecutive patients for evaluation of immune parameters. RESULTS Forty screened patients were eligible and evaluable for response, and 39 were evaluable for toxicity. 25 patients had asymptomatic and 15 symptomatic brain metastases. The toxicity was primarily grade 1-2 with no grade 4 or treatment-related deaths. Four patients had thromboembolic events grade 3. One patient obtained a CR and five a PR in the CNS, while two had CR and four had PR outside CNS. Overall response rate was 17.5%. We found a significant positive correlation between lymphopenia and objective response. CONCLUSIONS The combination treatment was well tolerated but with more frequent thromboembolic events compared to single drug TMZ or THA. The treatment demonstrated activity in CNS as well as outside CNS. The correlation between lymphopenia and objective response needs further investigation.