 I want to discuss a trial concept that came forward through SWAG and my collaborators at SWAG. Amato Zerita at Anderson, Elizabeth Heath at Carmanos, John Haymack also at Anderson, and Kathy Tangan are statistician. So I don't have to tell the people in this room about the scope of the problem in the U.S. There are close to 70,000 cases of RCC a year, and we know that nearly half of all patients will present with or develop metastatic disease, and we also know that up to 30% of patients will fail to respond to initial treatment of that disease. So choosing the optimal agent for frontline therapy is important, and it's also magnified in patients who have poor risk. It's a little interesting that in 2013, we know a lot about the targets for our therapy, but we still can't select patients. So biomarkers are really non-existent in terms of validating in a prospective setting. So with regard to biomarkers, we've discussed this a lot in the group, both within SWAG and also with our collaborators in the other adult cooperative groups. Tissue-based biomarkers are very appealing, but there are some problems. The intertumor heterogeneity, which we've discussed today, tissue preservation in a large cooperative group study, shipping and storage. Plasma-based biomarkers have a lot of appeal because they're straightforward and relatively non-invasive sample collection. They're robust analytical platforms for their measurement. It's easy to monitor changes in plasma-based biomarkers during treatment, and that gives you the potential for early identification of disease resistance. So there are some retrospective data for predictive markers for response to some of our targeted agents. Probably one of the nicest is this data from MD Anderson and GSK, looking at IL-6 in Pozopinib. And IL-6 in this study, which is published in Lancet Oncology, was found to be both prognostic and predictive for progression-free survival, and actually for overall survival as well. And there's also some nice data coming out of the Duke group, looking at LDH in a population of high-risk patients treated with Temserolimus or interferon, showing that elevated LDH above the upper limit of normal was predictive for response to Temserolimus. So there is some nice retrospective data there to follow up on. So what we proposed actually was a phase three biomarker trial, examining the benefit of plasma biomarkers to predict response to target therapy and frontline treatment of poor risk renal cancer. We would take newly diagnosed metastatic renal cell cancer by poor risk by the IMRCC criteria, stratified for nephrectomy versus local LDH. We would require both plasma and FFPE tumor tissue. The patients would be randomized to Pozopinib versus Temserolimus. And the endpoint would be a co-primary endpoint. Validating LDH and IL-6 is predictive markers for progression-free survival. And also looking at progression-free survival of the two arms, Pozopinib versus Temserolimus. IL-6 and LDH are the candidate biomarkers, but we'll test others on a platform as well. And the biomarkers would be integral to the study but not measured pre-randomization. Other biomarkers to be measured would be other plasma, cytokines and CAFs, SNPs and tissue-based biomarkers. There would be an interim analysis where we would evaluate for progression-free survival, but not the biomarker endpoint and then the final analysis. So key eligibility criteria would be some element of clear cell RCC. We would exclude chromophobe medullary, pure papillary or transitional cell. We decided actually in Orlando not to allow prior chemo or immunotherapy for metastatic disease, but patients who had received one of those therapies for adjuvant as long as they had been off of treatment for more than a year would be permitted. We had to have measurable metastatic disease. Nefrectomy would be permitted. Radiation therapy permitted so long as the patients had gone more than 14 days. No active CNS disease, but we would allow treated CNS disease if the patients were stable. Other key eligibility criteria really relate to the labs and the drugs themselves and the safety. So our schema for blood draws and imaging. I'll discuss in a minute. We're gonna have an early CAT scan to allay fears about patients progressing on an mTOR inhibitor versus a tyrosine kinase inhibitor. We'll draw blood at each of the time points for CAT scans and we'll evaluate the blood pretreatment and at progression and at one time point prior to progression as well. Again, as I said, we were going to allow a six week CT scan whereby patients with stable disease or better would remain on study, patients with progressive disease, but seeming to be deriving benefit would be allowed to continue on study. So the primary PFS assessment will be based on the three month scan unless the patient's removed at the six week point. Selection of biomarkers for inclusion. We're gonna have a biomarker committee to review potential biomarkers for inclusion. IL-6 and LDH will be included, but a number of other plasma markers may be included, including some that we've discussed today, IL-8, VEGF, some members of the FGF family, TMP1 and others. Subjects will be randomly divided into training and validation sets, and there'll be collection of peripheral blood monocytes to now for SNP measurement and tissue based biomarkers as well. Statistical design, we are assuming three years of accrual with one year of follow up. If we crew 562 patients, that will give us the power to examine not only progression free survival between the two arms, but also adequate power for Pozopinib versus Temseralmus comparison as well as detection of a reasonably sized treatment interaction for LDH and IL-6. Issues then discussed within the renal working group are the record three data. So after ASCO, we had to a little bit go back to the well and discuss the record three data and the relevance of this study after record three. So I know everyone is familiar with the record three study, Everolimus versus Sutent, and then crossover at progression, and the steady end points here were progression free survival in the front line. So everyone is familiar with what happened with all the patients in this study, Everolimus versus Sutent, but in the few patients in this study who were poor risk, Everolimus really wasn't inferior to Sutent, and the progression free survival as you can see was pretty poor, pretty short time to progression. So our thoughts about record three were despite the difference in progression free survival in the TKI versus the mTOR arm, there are still patients who obtain long term survival in the mTOR arm, and the meager progression free survival for poor risk patients really emphasizes the fact that the choice of front line drug is probably critical for those patients. It's unclear to me why so many patients didn't cross over to second line therapy, and one could argue that might be because the correct front line therapy wasn't chosen for them. And again, the value of a non-inferiority phase two trial that wasn't meant to be practice changing or definitive I think is arguable. Record three wasn't designed to validate predictive biomarkers for mTOR or VEGF TKIs, and this new study we're proposing will be the first ever to validate such biomarkers, and interestingly also at ASCO, the IL-6 data from the CALGB study with Bevacizumab provided additional support for IL-6. The patient population in our study will be different than the record three, and the treatment arms in the new study will also be different. And I think we've mitigated concern about early progression on the mTOR inhibitors by adding the early CT scan. So additional discussion was had about the choice of front line agents, and I think this is going to be a pragmatic trial looking at front line agents that are approved and that insurance will agree to and pay for. I think that the data from both the Pizopinib trial and the Bevacizumab trial show that plasma biomarkers are robust, and so I think that argument about the robustness of plasma biomarkers has largely been elated. And then finally, the long-term relevance of the VEGFTKIs and mTOR inhibitors was also raised in the renal working group, and the discussion ultimately centered around the fact that these drugs are not gonna go away, that they will be used in combination. It would be good to have biomarkers that we can use to assist with combination studies, and these drugs will likely be used in the second and third line settings as well, so still this data will be important. Thank you.