Topoisomerase enzymes play an important role in DNA replication, as they control the way the DNA winds. Winding too much or not enough would stop the replication process because another set of enzymes, the helicases, would be unable to separate the two strands.
Topoisomerase inhibitor drugs interfere with this activity, and result in both single and double stranded breaks that, ultimately, result in apoptosis. There are two forms of topoisomerase, I and II, and several anticancer agents act against topoisomerase I, including camptothecin, and its derivatives irinotecan and topotecan.
Nektar Therapeutics has now developed a pegylated tetrameric derivative of irinotecan that is designed to preferentially penetrate tumour vasculature ahead of normal vasculature. This leads to an increased concentration of drug within tumour tissues, and because it is a pro-drug that slowly releases active via hydrolysis as it is metabolised, gives continuous exposure to the active drug throughout the chemotherapy cycle. It has been given Fast Track development status by the US FDA for advanced breast cancer, and is also being investigated in ovarian and lung cancers, and glioma.
A randomised, two-stage, open label Phase II trial was carried out in 70 patients with metastatic breast cancer that had previously been treated with taxane drugs.1 Subjects were given 145mg/m2 every 14 or 21 days. A total of 20 patients achieved an objective response, with two complete responses and 19 partial responses. Ten of these were on each arm of the trial, with the two complete responses in the group dosed every 14 days.
The most common serious adverse events included delayed diarrhoea, fatigue, neutropoenia and dehydration, with 14 patients discontinuing as a result of drug-related toxicities, and there were two possible drug-related deaths in the 14 day group. The better adverse event profile in the 21 day group led to this schedule being chosen for a Phase III trial that is now underway, comparing etirinotecan pegol treatment with the treatment of the physician’s choice.2
In another Phase II trial, 71 patients with recurrent platinum-resistant or refractory epithelial ovarian cancer were given 145mg/m2 every 14 or 21 days until progression or intolerable adverse events occurred.3 There was a 20% overall confirmed objective response rate and a median response duration of 4 months, with the rates very marginally higher for those dosed every 14 days. The median overall survival was 10 months and 11.7 months respectively. It was well tolerated, with the most common serious adverse events including dehydration and diarrhoea. This was less common in the 21 day dosing schedule, and again this was selected for further studies.
Positive results have also been achieved in a trial in 20 patients with high grade glioma who had progressed after treatment with bevacizumab.4 These patients have an extremely poor prognosis, and in the Phase II, single arm, open label trial subjects with anaplastic astrocytoma or glioblastoma were given intravenous doses of 145mg/m2 etirinotecan pegol doses every 21 days as a single agent, with a median of three cycles. Two glioblastoma patients had partial MRI responses, with 10 patients achieving stable disease, the six-week progression-free survival rate was 55%, and the median overall survival from the first infusion 4.1 months. At the time these results were reported, two patients were still receiving treatment, one having had 9 cycles and the other 19.
References
1. A. Awada et al. Lancet Oncol. 2013, 14, 1216
2. E.A. Perez et al. J. Clin. Oncol. 2012, 30 (suppl.) Abst. TPS 1140
3. I.B. Vergote et al. J. Clin. Oncol. 2013, 31, 4060
4. S. Nagpal et al. J. Clin. Oncol. 2014, 32 (suppl.) Abst. 2096
