A randomised, controlled study to evaluate the effect of high-dose bosentan in patients with stage IV metastatic melanoma being treated with dacarbazine

Background: Evidence suggests that endothelin (ET) may play a role in the physiology of melanocytes and that the ETB receptor is upregulated in human melanoma. The oral dual ET receptor antagonist bosentan, indicated for the treatment of pulmonary arterial hypertension, may potentiate the effects of alkylating agents. An open-label, uncontrolled study suggested that bosentan may be of benefit in patients with stage IV metastatic melanoma. We therefore evaluated the potential benefit of bosentan combined with dacarbazine (DTIC) therapy in a phase II, randomised, double-blind, placebo-controlled trial. Methods: This event-driven study included 80 patients with histologically proven malignant melanoma (stage IV, RECIST criteria), ECOG performance status ≤2, no prior DTIC or other chemotherapy for stage IV disease, and no abnormal liver function tests or lactate dehydrogenase. Patients received intravenous DTIC 1000 mg/m² in 3-week cycles plus oral bosentan 500 mg bid or placebo. The primary endpoint was the time to tumour progression (TTP). Main analysis was on the all-randomised set. Results: No difference between treatment groups was observed for TTP (hazard ratio [HR] placebo over bosentan: 1.14, 95% 2-sided confidence interval [CI] 0.72–1.83), progression-free survival (HR 1.06; 95% CI 0.66–1.70), or overall survival (HR 1.04; 95% CI 0.58–1.87). Incidences of most adverse events were similar between groups, as were clinically relevant (≥3x upper limit of normal) increases in hepatic aminotransferases (10.5% placebo vs. 7.8% bosentan). A higher incidence of haemoglobin <10 g/dL was observed with bosentan (5.2% placebo vs. 31.5% bosentan). This was managed by dose adjustment of DTIC; discontinuation of bosentan was not needed. Conclusions: In this population of patients with severe stage IV metastatic melanoma, no treatment effect on time to tumour progression was observed with bosentan compared with placebo. No unexpected safety concerns or increased incidence of elevated hepatic aminotransferases were observed despite the high doses of bosentan used.