 Hello, my name is Martin Voss. I'm a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. My clinical area of expertise is treatment of metastatic kidney cancers. Today, I was asked to tell you about a clinical trial that my center is participating in. This is the DART study, and we're going to look through some slides here that I've put together to summarize what this clinical trial is about and what we have learned on it so far based on a presentation that was given at the annual ASCO meeting earlier this year. So this is a randomized study that is testing an approved medication exit nib in combination with a novel investigational agent called DeLandersept in patients with metastatic kidney cancer who have had prior treatment. If we go to the second slide, you can see here by a way of background that the standard of care for managing metastatic kidney cancer in 2014 is really the use of so-called targeted therapies, medications that work by inhibiting what we believe to be molecular mechanisms that are important for kidney cancer cell growth. If we understand the biology of the tumor cells, then we can find ways to inhibit that. The majority of the agents that are presently FDA approved in the United States work by blocking signaling through VEGF, the vascular endothelial growth factor, and essentially work by blocking blood vessel growth, which we know is of principle importance to kidney cancer biology. We have a number of these medications that are quite effective, but unfortunately do not work for every patient, and for those patients that do have a good response, durations are not always durable, meaning that cancer cells can grow despite of these medications. So we see a cartoon here that illustrates how patients can experience progression of their cancer despite being treated with these blood vessel inhibitor agents. In the top part of this image, you can see that some patients have a good response where blood vessel growth is effectively inhibited and tumors shrink, but eventually the tumors find ways around the medication to develop other mechanisms of building new blood supplies. At the bottom part of the imagery here you see that some patients never quite respond to these treatments at all, which essentially means that their tumors build blood vessels that do other molecular mechanisms than the ones that we are inhibiting with the medications. So if we go back then to look at all the medications that are approved, we have to think about ways to treat patients for which the first agent we have tried has failed. And I've highlighted here for you a medication called Exitinib, which is approved in patients who have previously had other medications, primarily blood vessel inhibitors. So the large trial that led to the approval of Exitinib was conducted only in patients who had been on other medications, meaning Exitinib was proven to be effective even when other VHF inhibitors had failed. So that is our present approach to these patients using other medications in that setting. And if we want to improve upon that principle then maybe we have to go back and look at the biology of these cancers again and understand blood vessel growth better. So here we have a cartoon that shows you that blood vessel growth is obviously a very intricate process that happens in different stages. The medications that we use all work the VHF, which is really most important for the initial stages. Tumors to create these factors to initiate growth of new blood vessels, which you see in step one and then step two. But once these blood vessels have grown, there are various other mechanisms that are important for the maturation of these new blood vessels and that is presently not addressed with the medications that we have approved. So approved medications really block steps one and two and maybe at this time that we try to look into novel approaches to also interfere with the later stages of blood vessel growth. Here we come to talk about the investigational agent in this trial, the Lanter sebaceous medication that does not target blood vessel growth by VHF, it targets it through another molecular mechanism. So from a different angle, so to say, the ALT-1 pathway is a molecular signaling pathway that is important for maturation of newly formed blood vessels. The Lanter sebaceous on its own has been tested in clinical trials because the number of malignancies and it's been found to be effective and safe in many different cancers. So if we go back to our cartoon then talking about patients who have experienced failure to their initial treatment with blood vessel inhibitors, the present approach would be to use medications like ExitNIP that have been shown to be effective by using a very similar approach to the first medication the patient had been on, meaning blocking VHF again. An alternative approach might be to use a medication like the Lanter sebaceous that blocks blood vessel growth from a different angle. That said, maybe we could be even more effective if we took a more aggressive route and actually combined these two approaches together and that's what this clinical trial is exploring. So combining ALT-1 and VGF inhibition, we argue might be more effective than doing the two either alone or in sequence. And this has been tested and proven to be successful in laboratory experiments for kidney cancer and other models. One thing that is important whenever we consider combining two different medications is do these medications have similar side effect profiles, meaning if you give two medications that each by themselves cost one side effect then you might see a lot of that side effect if you combine them together. So that is something we try to avoid and it's important to note that the Lanter seb actually has a side effect profile that is different from that of the medications we presently have approved. So it's a good candidate for combination with medications like Exitinib and ultimately we're hopeful that this might be more effective to overcome the resistance to VGF targeted therapy that patients have developed and just using another VGF targeted agent like Exitinib alone. So that leads us to the actual trial that we're discussing today. So the DART study is the phase two randomized double blind study that compares the combination of this new medication to Lanter seb and the approved medication Exitinib. It's a placebo controlled trial so on this trial there are patients who are getting the Lanter seb plus Exitinib and there are patients who are getting a placebo together with the Exitinib. What's important to point out is that every single patient going on this trial is receiving Exitinib therapy so no one is receiving Exitinib alone. Here we have an overview of this study design and this study is being conducted in two parts. The first part is actually already completed and we are now enrolling to the second part. The first part was a phase one segment that essentially was designed to determine the optimal dosing schedule for combining these two agents to make sure that it was safe to give them together and to find out how exactly one best gets them in combination. That information is now available to us and has helped us to design the second part which is now the randomized piece giving patients the combination versus Exitinib plus the placebo. We do know a lot about the combination at this point given the part one that we have already completed and Dr. Atkins from Georgetown University one of the participating investigators on this trial presented some of this data at the 2014 ASCO meeting in Chicago so I have a quick overview for you here. So part one has treated 26 patients with this combination. We found this overall to be reasonably well tolerated by patients. The most common side effect for the combination was fatigue. Other side effects that we did note are listed here diarrhea, mild impairment of kidney function. There was no one with serious kidney failure on this part one segment. Poor extremity swelling which we believe is probably an effect of the delantercept, something we don't typically see with the Exitinib force in this mild intermittent nosebleeds, GI distress, cough, and worsening of hypertension which is the very common side effect of Exitinib. One thing that is important to make that the last bullet on this slide is that the Exitinib toxicity profile that we are used to seeing this being a standard medication that we use in our patients all the time was not exacerbated by the addition of delantercept meaning we did see the typical Exitinib side effect. We did not see the metahier frequency or at worse intensity. We do have some sense for the activity of this combination. Obviously we did report the anti-tumor efficacy for these first patients treated on the trial. This is available for 20 patients, that's one you can see that there are patients with partial responses seen on the study. Many patients, more than 50% of our population on this trial had extended disease control on this trial so certainly this would be considered very promising early data that makes us excited to bring patients onto the second part of the study. We have an overview here of part two now so this is a trial that is presently open at 13 sites within the U.S., we plan to expand to various other sites, likely about 40 hospitals in total will be accruing patients to this. Patients to be considered for this study would be those with renal cell carcinoma with predominant clear cell phenotype, so predominant the clear cell renal cell carcinoma, patients can have had one line of prior targeted immunotherapies which should be either submit-nip or presopenip, these are the two most commonly used agents in the first line setting, patients can be considered if they've had prior immunotherapies such as IO2 or a newer immunotherapy on a clinical trial. This is a large trial that will enroll about 130 patients that will be randomized one-to-one to receive either the combination of exit-nip plus the lantercept or standard exit-nip with placebo. This randomization will be conducted by a computer, this will be blinded meaning neither the treating physician nor the patients will know whether they are on the injection for the lantercept or the placebo. Exit-nip is an oral medication that is administered by mouth on a twice daily schedule, patients do that at home. The lantercept is an injection medication that is given by injection under the skin, called a subcutaneous injection in the office every three weeks for patients that are randomized to the placebo arm, an injection under the skin is essentially just a carrier solution without medication. The study end points for this is obviously now looking into the question whether exit-nip alone versus exit-nip plus the lantercept is different in terms of how well disease is controlled and how long patients can stay on one treatment until they sequence to the next. At its ability I have mentioned, again this is to be predominantly clear self, patients must have measurable disease, meaning there must be something on scans that we can follow to assess the response and that is measurable by research standards and again patients must have been treated with either the exit-nip or the open-nip. They can have had one of these agents and immunotherapy before. There are some considerations in terms of other medical history that we include for safety purposes and those are listed here also. For those listeners that are interested to learn more about the trial, as usual, clinicaltrials.gov is a terrific resource. The study identifying numbers listed here and can be entered into the search field in clinicaltrials.gov to identify the study, find participating centers, including phone numbers to arrange for consultations to ask more questions, the eligibility criteria and so forth are also listed on this governmental website. Thank you very much for your kind attention and have a good day.