This clinical trial was an investigator initiated trial supported by the NCI and CTEP. It was based on the preclinical data from our lab showing that a combination of entinostat, one of the oral histone deacetylase inhibitors, had a synergistic effect in combination with high dose interleukin-2 in a mouse model of kidney cancer. So we were able to translate these biological results in a clinical trial in patients with clear cell carcinoma where high dose interleukin-2 in a selected patient population might be an option.
How many patients were involved?
To date we have accrued 47 patients through a phase I, a short phase I, and then a phase II. Four patients were not evaluable for efficacy but we included all patients for toxicity assessment. There are still some patients that haven’t completed the first cycle of therapy, that is 85 days for tumour assessment.
What have you found so far?
We’ve been encouraged to see an objective response rate that is approximately 35%. We had so far ten patients with partial response and three patients with complete response and a median progression free survival of 16.1 months. So this is, as compared to historical control with high dose interleukin-2 alone, it’s promising because the historical data suggests more a 25% response rate, although based on the WHO criteria, and a median progression free survival of 4.1 months.
What about toxicity?
Toxicity high dose interleukin-2, of course, is a quite toxic regimen, the patient needs to be admitted to the hospital but we haven’t seen an overlap in toxicity between the HDAC inhibitors and high dose interleukin-2. For example, we saw, this is a class effect from HDAC inhibitors but we haven’t seen increased cardiac toxicity, hypertension or the traditional toxicity that would be seen with the high dose interleukin-2. So overall we believe this combination is relatively safe, of course it has to be given in the centres that are equipped to give high dose interleukin-2.
What is the take home message so far?
This is the first example of what we call an epigenetic therapy that can modulate immunotherapy or other traditional therapies. So we are very excited at perhaps this, we believe, positive result. Of course it needs to be validated, probably in a larger randomised trial but it really sheds some light on the potential of using epigenetic drugs, drugs that affect the epigenome, the gene expression, as immuno-modulators. So as immunotherapy is becoming really the standard of care for several diseases, we believe that this example of a combination with high dose interleukin-2 provides really the platform to test also some additional combination strategies, not only in kidney cancer but also in other solid tumours.
