WIN Symposium 2013

Latest on the WINTHER trial

Prof Jean-Charles Soria - Institut Gustave Roussy, Villejuif, France

I act currently as the co-ordinating PI of the multi-institutional, multi-centric WINTHER trial which is the first therapeutic trial that has been pushed by the WIN consortium.

So what are the aims of this trial? It’s a new type of trial.

Correct. WINTHER is probably what we could call a second generation personalised medicine trial. In basis the aim of WINTHER is to try to provide a biology-oriented therapy to the vast majority of patients that are enrolled in the trial. Let me explain to you what does that mean. Standard of care is usually a biopsy and pathological analysis and then therapy that is based on the pathology and the organ where the tumour sits. First generation personalised medicine trials are trials that will either offer an all-purpose biopsy of the tumour or analyse archive material. What they analyse in the vast majority are structural DNA changes meaning mutations or translocations, amplifications, deletions. When you put together all these structural DNA changes they are present in only 30-40% of patients meaning that when you offer a first generation personalised medicine trial you sell the dream of precision medicine to the patient and you fail the dream in 60% of the cases. So WINTHER aims at tackling that problem and trying to have a vast majority of patients being biology oriented. To do so it integrates on top of the on-purpose tumour biopsy, which is usually a biopsy of a metastatic site, a biopsy of the matched normal tissue. In doing so we will have not only the structural DNA changes but we will also have in patients for which there are no structural DNA changes the capability to measure the transcriptomic distance of genes between the tumour and the matched normal tissue, therefore transforming that transcriptomic distance in potential matches for registered or not registered drugs that are in development. We have, therefore, two arms in WINTHER: arm A which are patients for which the therapy is guided by the structural DNA changes. That arm A we have a specific partner, which is Foundation Medicine, providing clear, certified, deep sequencing on Illumina based platforms and on arm B we have a partnership that is currently for the EU sites and Israel, an Agilent based platform which is the Gustave Roussy platform led by Vladimir Lazar. We measure there the transcriptomic changes to orient for the therapy.

So these transcriptomic changes, what does it mean for treatment?

Transcriptomic changes are just measuring different genes for a patient. It’s extremely simple to illustrate that by taking one example: for instance, we measure in the tumour many genes and let’s say that we measure the fact that thymidylate synthase and dihydrofolate reductase are extremely high in the tumour as compared to the normal tissue. The measurement of these changes will be put in an algorithm that matches transcriptomic changes to drugs, because we know that the drugs have specific targets and therefore those targets are integrated in the algorithm. We know, for instance, that pemetrexed has as main targets dihydrofolate reductase and TS, so the algorithm is going to tell you probably pemetrexed is an extremely good match for this patient. Another example – you might measure in the tumour extremely high levels of VEGF, vascular endothelial growth factor, which is the target of bevacizumab. The algorithm is going to tell you maybe bevacizumab. So this is our research algorithm that can only be used in the setting of a prospective clinical trial. But we are orienting therapy in a little more than half of the patients through the use of these transcriptomic measurements and the use of the algorithm.

So this is half of the 60% that don’t have structural changes?

No, in fact arm B applies to the 60% of those who have no structural DNA changes. So in theory you enter the trial, 40% will have structural DNA changes, 60% will be oriented through the algorithm. But the reality is not 100% of the patients that get into WINTHER will have a biology oriented therapy because to do so you need to succeed very high yields of tumour cells in the tumour biopsy and in the normal matched biopsy. We are going to have probably 10-20% of patients who will fail the biopsy because we’re going to have tumour cells that are at too low a threshold to make the call.

At this time this 10-20% will just get standard chemotherapy?

Those ones are considered as screen failures for the trial so they are not in the trial.

And the funding for this trial?

OK, so let me clarify first the partners for the trial and then we’re going to go on the funding. So there are, in theory, six academic clinical settings where the trial is going to be implemented. Right now it’s active and recruiting in Gustave Roussy in Paris, France, the Sheba Hospital in Israel and we believe the third site that will be activated pretty soon, because it has all the regulatory approvals, is Vall d’Hebron Institute of Oncology in Barcelona. Then we have three other sites that are in North America that have yet to be activated: MD Anderson Cancer Center, University of California in San Diego and the Segal Centre in Canada. These six academic sites are partnered with technology providers, so Foundation Medicine is the provider for deep sequencing and next generation sequencing for structural DNA changes and, as I said, we have the Agilent platform at Gustave Roussy for the transcriptomic changes. For the US and Canada sites we need a platform that can measure these transcriptomic changes in a clear certified environment in North America which we are currently defining at this standpoint. Then when it comes to the financing, as you know this is an initiative that is pushed by the WIN consortium. Most of the funding at this time point is coming from an FP7 EU grant that has been obtained. On top of that significant amount of funding, which is the principal cornerstone funding of this trial, we have obtained a research grant from some pharma companies, namely Pfizer and Novartis, and hopefully pretty soon from Eli Lilly and the Breast Cancer Foundation also which is, as you know, a non-pharma initiative supporting this trial.

So at which stage are you in the trial? Are you already analysing patients?

The trial aims at recruiting 200 patients, it has been opened for recruitment in April 2013 and as of July 2nd 2013 35 patients consented to participate in the trial. It means that we are putting 2-3 patients per week in the trial.

Which types of tumours?

As you can imagine, having a matched normal tissue allows only certain tumours to be enrolled but at this time point we have enrolled lung cancer, breast cancer, kidney cancer, some rhabdomyosarcomas and head and neck squamous cell carcinomas. There are tumour types for which it will be impossible for us to enrol them like ovarian cancer. We’re not going to go to biopsy the normal ovary because that’s very challenging technically and ethically but it’s an initiative that is not restricted to a single tumour type.