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

Abstract

Background: The endothelin system is implicated in the pathogenesis of melanoma. We evaluated the effects of bosentan - a dual endothelin receptor antagonist - in patients receiving first-line dacarbazine therapy for stage IV metastatic cutaneous melanoma in a phase 2, proof-of-concept study.

Results: Eligible patients had metastatic cutaneous melanoma naïve to chemotherapy or immunotherapy, no central nervous system involvement, and serum lactate dehydrogenase <1.5 x 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 < or = 10 g/dL and < or = 8 g/dL was more common in the bosentan group.

Conclusions: 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.

Trial registration: This study is registered in ClinicalTrials.gov under the unique identifier NCT01009177.

Figure 1

Patient flow through the study. Patient flow through the study: ¹Including adverse events relating to disease progression; ²Unrelated to disease progression; ³Includes one patient in each group who discontinued due to study closure; ⁴Efficacy was analyzed on the all-randomized set; however, one patient, randomized to placebo, did not receive any study treatment, had no post-baseline tumor assessments, and had data missing for the date of randomization at the time of database closure. Because time-to-event analyses required a randomization date, this patient could not be included in these analyses, including the primary endpoint.

Figure 2

Primary and secondary efficacy endpoints: Kaplan-Meier estimates of time to progression and overall survival. Kaplan-Meier estimates of A) time to progression and B) overall survival (all-randomized population).