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


BACKGROUND
This study is registered in ClinicalTrials.gov under the unique identifier NCT01009177.
Kefford
Richard F
RF
Westmead Institute for Cancer research and Melanoma Institute of Australia, University of Sydney at Westmead Hospital, NSW 2145, Australia. rick_kefford@wmi.usyd.edu.au
Clingan
Philip R
PR
Brady
Benjamin
B
Ballmer
Andrea
A
Morganti
Adele
A
Hersey
Peter
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077300:Bosentan; D003606:Dacarbazine / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects
D013449:Sulfonamides; D003606:Dacarbazine; D000077300:Bosentan