8-May-2012

Anticancer agent – verubulin

Abstract

The treatment of glioblastoma is still largely reliant on chemotherapy and radiation therapy. However, chemotherapy is all too often ineffective, partly because these cancers can be fairly resistant to drug treatment, but also because of the difficulty of getting cytotoxic drugs delivered to the tumour across the blood–brain barrier.

The treatment of glioblastoma with chemotherapy is often ineffective, partly because these cancers can be fairly resistant to drug treatment, but also because of the difficulty of delivering cytotoxic drugs to the tumour across the blood–brain barrier.

A new drug, verubulin, being developed by Epicept in collaboration with Myrexis, looks to overcome some of these problems.1 It acts as a microtubule destabilising agent, causing the arrest of cell division and apoptosis in cancer cells but, unlike other drugs that act via this mechanism, in animal studies, it was shown to cross the blood-brain barrier, reaching concentrations in the brain as much as 30 times higher than that seen in the plasma.

Verubulin

In one trial, patients with glioblastoma multiforme in their first or second relapse were given doses of 2.1, 2.7 and 3.3mg/m2 as a 2-hour intravenous infusion every two weeks of a six-week cycle, or three weeks of four.2 They were also given intravenous carboplatin. Three of 19 patients experienced a grade three or greater adverse event related to treatment, including pyrexia, transient ischaemic attack and thrombocytopoenia. Two achieved a partial response, and a further six stable disease. The median progression free survival time was 1.8 months. No incidence of cerebral haemorrhage was reported despite this being a highly vascularised form of tumour.

A Phase II study has also been carried out in 31 patients with recurrent glioblastoma who had not previously been treated with bevacizumab but had failed standard prior therapy.3 All had undergone tumour resection, and a median of two prior chemotherapies, upfront with radiotherapy and rescue. A dose of 3.3mg/m2 was given as a 2-hour intravenous infusion once a week for three consecutive weeks in a four-week cycle. The median number of cycles completed was two, with a range of 0 to 12, and three completed fewer than two cycles of treatment and were not evaluated.

The most common adverse events were fatigue, nausea and constipation. Four subjects experienced a progression-free survival of at least six months, with three achieving a partial response and a further seven stable disease. The median duration of stable disease was 3.9 months. Trials continue.

references

1. N. Sirisoma et al. J. Med. Chem. 2009, 52, 2341

2. K.F. Grossmann et al. J. Clin. Oncol. 2010, 28 (suppl.), Abst. 2095

3. L.J. Kim et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. 2088

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