A randomized, double-blind, placebo-controlled study of high-dose bosentan in patients with stage IV metastatic melanoma receiving first-line dacarbazine chemotherapy

Eligible patients had metastatic cutaneous melanoma na？ve to chemotherapy or immunotherapy, no central nervous system involvement, and serum lactate dehydrogenase <1.5 × upper limit of normal. Treatment comprised bosentan 500 mg twice daily or matching placebo, in addition to dacarbazine 1000 mg/m2 every three weeks. Eighty patients were randomized (double-blind) and 38 in each group received study treatment. Median time to tumor progression (primary endpoint) was not significantly different between the two groups (placebo, 2.8 months; bosentan, 1.6 months; bosentan/placebo hazard ratio, 1.144; 95% CI, 0.717-1.827; p = 0.5683). Incidences of most adverse events and clinically relevant increases in hepatic transaminases were similar between treatment groups although hemoglobin decrease to >8 and ≤ 10 g/dL and ≤ 8 g/dL was more common in the bosentan group.In patients receiving dacarbazine as first-line chemotherapy for metastatic melanoma, the addition of high-dose bosentan had no effect on time to tumor progression or other efficacy parameters. There were no unexpected safety findings.This study is registered in ClinicalTrials.gov under the unique identifier NCT01009177.Each year there are approximately 160,000 new cases of malignant melanoma worldwide and it is responsible for an estimated 41,000 deaths [1]. The incidence is currently increasing and predicted to continue increasing for the next 20 years or more [2]; mortality is also increasing in many countries, including Europe and Australia [3]. The prognosis for patients with distant metastases from melanoma is poor; patients with elevated serum lactate dehydrogenase or extra-pulmonary visceral involvement have a median survival of just 4-6 months and a 2-year survival rate of ≤ 5% [4]. No systemic therapy has been shown in phase III trials to be superior to single agent treatment with dacarbazine. However, response rates of only 8-15% have been reported for this approach in randomized controlled trials [5-10].