Malignant melanoma - elesclomol
Melanoma is a malignant tumour of the melanocytes and while it is one of the less common forms of skin cancer, it is responsible for about three-quarters of all skin cancer deaths - the World Health Organisation estimates that it kills about 50,000 people a year.
Melanoma is a malignant tumour of the melanocytes and while it is one of the less common forms of skin cancer, it is responsible for about three-quarters of all skin cancer deaths - the World Health Organisation estimates that it kills about 50,000 people a year.
Its deadliness results largely from its tendency to metastasise rapidly. If it is caught early and removed by surgery, then 90% of patients are likely to survive. If not, the prognosis is poor, and drug treatment options are limited.
A new treatment idea is based on the fact that mitochondria produce higher levels of reactive oxygen species under hypoxic conditions, such as in tumour cells. The accumulation of these species in the tumour cells ultimately results in apoptosis, so drugs that promote the formation of reactive oxygen species may have therapeutic use in cancers such as melanoma. Synta Pharmaceuticals, in conjunction with GlaxoSmithKline, is developing elesclomol, which triggers this effect. It has showed particular promise in combination with taxanes in preclinical models.
Several trials have been carried out in different cancers. These include a Phase I/II study where patients with advanced metastatic melanoma were given the drug in combination with paclitaxel.1 In the initial phase, three patients were given 80mg/m2 paclitaxel and 106mg/m2 elesclomol once a week for three weeks of a four week cycle, and three given the same schedule but 213mg/m2 elesclomol. No dose limiting toxicities were seen, and the study was expanded to 20 patients at the higher dose; the expected adverse event profile for paclitaxel was observed. Eleven of the 20 patients achieved stable disease.
The second stage of the trial was double blind and randomised, and 81 patients with metastatic melanoma were given both drugs or paclitaxel alone; the control patients could cross over to the active arm on disease progression.2 Progression free survival was 3.7 months for the elesclomol group, and 1.8 months for the control. Those given the combination had a response rate of 15%, compared with 3.6% for those on paclitaxel alone. A retrospective analysis of overall survival showed that those given elesclomol had an overall survival of between 12 and 14.3 months, and 5.6 months in those who did not cross over.3 A Phase III trial is underway.