AML is a disease that approximately 20,000 patients are diagnosed in the United States. In the last two years there are a lot of targeted therapies approved for AML but still for younger and fit patients we’re still using the cytotoxic therapies. So the background for this study that we were using this immunotherapy agent, essentially combining it with the backbone of the chemotherapy, trying to break the tolerance of the immune system against the cancer cells. So that was essentially the background – can we add an oral agent which is a special inhibitor of the IDO pathway, we call them, indoleamine-dioxygenase, and turn on your immune system against the cancer cells with the help of the chemotherapy.
What was the method?
This one was a phase I study; I believe we delivered the premise of the phase I. The primary objective of the phase I was to measure the safety and tolerability of this oral agent, the name is indoximod, adding it to the backbone of chemotherapy. We found that there was no toxicity essentially, we’re calling it regimen limiting toxicity, so the adverse events that we see are very consistent with the backbone of chemotherapy plus AML. We used to read this as a phase I dose escalation, we wanted to find out what is the recommended phase II dose or the maximum tolerated dose. We tested three different dose levels – we had 600mg, 1,000mg and 1,200mg to be taken orally every eight hours. Now we know that the 1,200mg is tolerable and safe and it’s a recommended phase II essentially.
The study is a phase I, we are still ongoing. We are in the dose expansion – we want to understand a little bit more about the clinical activity of this combination of this drug with the chemotherapy.
Is there anything on clinical efficacy to report?
As I told you, the important part, the premise of the first one, was the safety and tolerability and we found that. From the clinical activity we are very encouraged, it’s very, very promising. We found that approximately 73% of people achieved complete remission in this study and we have an almost unprecedented rate of achievement of MRD negativity, minimal residual disease negativity, post-induction which is 86% and post-consolidation 100% of our patients in our per protocol population they achieved MRD negativity. A few notes – it’s important that the MRD measurement was centralised by Dr Mike Loken laboratory in Seattle and the MRD we measured it by flow. The level of MRD is less than 0.02%, that’s very, very important because it’s a very sensitive test. The second thing that’s very important is that our patient population, I present that today, 60% of them have adverse risk category by European LeukemiaNet, 60%. That is testimony by looking at seven of our patients, they had T53, they had RUNX1 or Axl1, eight patients, and twelve patients had NRAS mutations, this is a very heavily cytogentically and mutationally poor prognostic risk. So having this level of complete remission also with MRD negativity is extremely encouraging. Of course this is a single arm study, isolating the effect of the drug is impossible so we have to do a randomised study further on, but the importance is that in a very difficult disease to treat in this combination so far provided very significant and promising initial clinical activity.
Finally, it’s important that in this patient population, because this is a phase I study, we went after per protocol population and our definition of that is people that receive 80% of their remission, because we are after the regimen limiting toxicity. I cannot give you one dose of the drug and then if you don’t have the toxicity I say, ‘Oh my drug is safe.’ So you have to at least have some certain, some percentage, which is pre-specified in the protocol. People that receive at least 80% of the population, these are the people that we can judge them if the drug caused toxicity or if we see any efficacy we like saying, ‘It was in this population.’ If you have received less than 80% we’re still keeping you for some safety study but I don’t think it’s fair scientifically or clinically that we judge those patients. We call them intention to treat but they didn’t have it because of a different variety of reasons, not necessarily toxicity – people withdrew consent or they had sepsis, they could not swallow. Those people are not included either in the safety or efficacy and that’s very important to note.
What is the next step?
That’s a very good question. This is a phase I study, of course, and I said that it has delivered this premise but the important part is that I cannot sit here and say, ‘Oh, we are going to change how we treat AML.’ So the next step, I’m hopeful that we can do some randomised trial. This generated that it’s safe and the result is very efficacious, I got a lot of positive feedback from my other colleagues in the leukaemia community, so we are hopeful that we do a randomised phase II study and we tease out or isolate the effect of this agent when we are combining with the backbone of chemotherapy.