Vosaroxin is a first in class anti-cancer quinolone derivative. It’s a drug that has been evaluated in pre-clinical studies in AML cell lines and patient samples and has shown to be effective and has shown to be synergistic with cytarabine. It does have a few characteristics that make it particularly interesting, that is it is not a P-glycoprotein substrate and its activity is independent of the p53 mechanism and it has limited reactive oxygen species formation which differentiated it from anthracyclines in terms of reduced potential for cardiotoxicity.
So VALOR was a phase III randomised double-blind placebo-controlled trial. The patients were randomised on a one-to-one basis. They did get stratification based on age above and below 60, duration of first remission and whether they were treated in a US or non-US centre. There are two regimens where cytarabine at a dose of 1g/m2 daily for five days plus vosaroxin at 90mg/m2 on days one and four and this was based on a previous phase II study that was recently published by Jeff Lancet. The control arm was cytarabine alone and patients could get one or two induction cycles and those in remission would get one or two consolidation cycles. The primary endpoint of the study was overall survival with a number of secondary and tertiary endpoints that you see here on this slide.
I’d like to go over the eligibility criteria because it’s important because the design of this study was very well thought of and the patients were homogenised as much as possible. So they could go on this study if they were refractory, that means they didn’t achieve a remission to their induction therapy, or had a short duration of first induction which was less than 90 days. Patients could go on this study also if they were first relapse and they were categorised as early first relapse with a CR 1 duration of 90 days to one year or late first relapse with a CR 1 duration of one to two years.  Importantly, all these patients had to have received at least one cycle of cytarabine and anthracycline based induction therapy and also importantly they could not go the study if they had received more than 5g/m2 of cytarabine within 90 days of randomisation or had undergone an allogeneic or autologous transplant within 90 days of randomisation.
This is the primary endpoint of the study which is overall survival. You can see the overall population enrolled on the study was 711. This is one of the largest studies in AML and probably the largest study in relapsed AML. As you can see, the median survival for the vosaroxin and cytarabine arm was 6.7 months versus 5.3 months for the control arm with a p-value of 0.06. Now, using a stratified log rank analysis, which is a very commonly used analysis and is actually the analysis that’s used for most of the solid tumour trials, the p-value was 0.02.
Looking at the responses, the patients who were on the vosaroxin and cytarabine arm had a 30% overall CR rate as opposed to about 16% for the control arm. If you look at this among all the stratifications this was superior for the vosaroxin arm in all of them with perhaps the exception of patients under 60 where the difference was not as great. If you look at all the responses, again the advantage was clearly superior for the vosaroxin arm of the study.
Now, a large proportion of patients underwent an allogeneic stem cell transplant, overall about 30%, and if you divided by age patients over the age of 60 there was a 20% transplant rate after completing therapy versus for the patients younger than 60 about 45%. That’s actually a very high transplant rate in the relapsed setting. When you censor the data by allogeneic stem cell transplant you can see that again there is a statistically significant advantage for the vosaroxin and cytarabine arm with a p-value of 0.02.
If you look at the various strata that were included in this study, patients above and below 60, you can see that there is a clear advantage for the patients over 60 with a p-value of 0.06. I would like to emphasise the point that this population, patients over the age of 60, accounted for two-thirds of the patients randomised on the study, 451 patients, which clearly is a very large study on its own. Among the patients younger than 60 there was no advantage for the vosaroxin arm. Again if you look at the first CR duration stratification a clear advantage was seen in the elderly relapsed population, that’s those whose first remission was more than 90 days and less than one year.
What about toxicity and mortality? There was a higher incidence of toxicity in the vosaroxin arm but we were pleased to see that this was essentially all related to myelosuppression and there was no difference in the two arms of the study in terms of organ toxicity. More importantly, the increased toxicity seen on the vosaroxin arm did not translate to any increase in mortality with both 30-day and 60-day mortality being equivalent in the two arms of the study.
So, in summary, the combination of vosaroxin and cytarabine is associated with a survival advantage as compared to cytarabine alone, a higher CR rate with a very strong p-value and no difference in 30-day or 60-day mortality. So this is, again, one of the largest studies or randomised studies in the relapsed and refractory AML setting. There is a clear improvement in overall survival, particularly for the patients over the age of 60. There was a high post-treatment transplant rate and this could obviously underestimate any benefit for the vosaroxin arm because of the high transplant rate. In my opinion these data support the use of this combination as a new standard for salvage therapy in older patients with AML