WINTHER is the first signature trial from the WIN Consortium. It was conceived probably around 2011, 2012 and it’s a unique trial. The first thing is that it was international. The principle investigators included really good investigators from France, Spain, Israel, Canada and the United States. So just co-ordinating that was a pretty amazing experience. The other unique aspect of it is that it included a DNA arm, and that was foundation medicine, a really robust next generation sequencing assay, but also for the first time ever, to my knowledge, it included arm B which was an RNA arm, an arm where we used transcriptomics to navigate patients to drugs.
What was surprising about the RNA arm of this research?
Overall there were several surprises there. I want to start by saying that we did the RNA in a very unique way which is essential for further trials and that is that we compared the tumour expression to the expression in the normal tissue. To my knowledge that’s not usually done but we now know that that’s critical because the normal expression can vary tremendously from individual to individual. So, for instance, if you say that there’s a high level of a certain target you don’t really know that that level is high in the tumour if you don’t have the normal comparison because it’s really the distance between the normal and the tumour that is the critical parameter.
So what was really interesting to us is that the response rate in the RNA arm was actually higher than in the DNA arm. To me that was a complete surprise. We know so much about the targetable genomic abnormalities and I would have assumed that the response rates would have been higher in the DNA arm but it was just the opposite. Now, there were small numbers of patients in each arm so it’s not statistically higher in the RNA arm but numerically it’s higher and I wouldn’t have expected that.
How was the multivariate analysis done?
The statistics, this was a pretty intense job, I want to give the credit here to Jack Lee who I think is one of the best statisticians in the world. He’s at MD Anderson Cancer Center, very well known for his knowledge of statistics and his expertise in innovative trials. So he helped us put the statistics together. For us, what was one of the really interesting aspects was we did an analysis, a post-hoc analysis, blinded, to see how well patients were actually matched to their biologic characteristics. We needed to do that because physicians were able to choose the therapy and sometimes for practical reasons or because or comorbidities they chose maybe not the best biologic match. So we did this matching score to see how well was each patient’s tumour matched with the therapy that they actually got. Here the results were quite interesting – the better matched biologically, the better the patient did. That included higher responses, longer progression free survival and, very interestingly, longer overall survival as well.
How did you use the patient as their own control?
That was a very important aspect. When we planned the trial we had very ambitious goals and we used what is the Von Hoff. Dan Von Hoff created this model where you could use the patient as their own control. What we know normally happens in cancer is with each subsequent line of therapy the progression free survival gets shorter. So what we wanted to see was that the progression free survival on the WINTHER regimen would be longer than on the immediately prior regimen. We had the pretty ambitious goal that the ratio of the PFS on the WINTHER trial to the prior therapy, a ratio of 1.5 would be seen in 50% of patients on arm A and 40% on arm B. We actually didn’t achieve that. About 25% of the patients achieved that goal but not quite the 40% or 50% that we anticipated. That’s why we went on to look at some of these other analyses and some of these other endpoints.
What is being learnt from the WINTHER trial for the SPRING trial?
WINTHER taught us how to implement and how to execute an international trial, how to make it work, how to bring investigators from all over the world together to collaborate. That might sound simple but it’s actually a huge undertaking. So we have all the policies in place and the practices in place to do a trial. We also learned how to properly process the tissues, how to do the DNA, how to do the RNA, how to create a clinical management committee that brings the investigators from all over the world together. So that allowed us to move forward to the next generation trial and, really, SPRING is the next generation trial. Here we go from single agent therapy to a tri-therapy which is a triplet – three drugs together. Why three drugs together? In other diseases like AIDS and certain types of leukaemia one drug or two drugs is often not enough but putting three drugs together begins to have a huge impact on those diseases. We think the same thing will be true in cancer.
This trial, we went to the FDA, I felt that they really embraced it and helped us to get it off the ground. With a lot of help from others – these are Pfizer drugs, Foundation ARC has helped us fund it – we’ve been able to get the IND on the trial and to launch the trial and we’ve already treated three patients so we’re very happy with the movement that has occurred.
Tell us about the first patient in the SPRING trial.
The first patient was treated over a month ago and this patient is, I believe, 80 or 81 years old and she was treated by Dr Benjamin Solomon who is Dr Brian Leyland’s group at Avera. They’ve taken a huge leadership, we’re all here, and they put the first patient on the trial. Now, of course, one of our concerns is that the patient is 80 years old and we’re giving for the first time this new combination of drugs. But we know that a month in the patient hasn’t had any serious side effects so we feel very comfortable. There are now another two patients that have begun therapy but they’ve begun much more recently so we don’t know what has happened to them yet. But we think that this is really an excellent start.
What’s the timeline for SPRING?
We would expect that the phase I would take about a year, that would be quite standard. We have several different sites involved and a year to complete the phase I. The phase I is where we do dose escalations to look at toxicity. We’ll also be looking at responses but we definitely want to see how do these patients tolerate the drugs and what is the right dose of the drug, or the three drugs, for these patients. We would then move on to the phase II and the plan is to move directly from the phase I to the phase II probably as a single trial. In the phase II we would anticipate that we would treat up to about a hundred patients to get a better idea of the efficacy.
