 So our next talk prior to our panel discussion is by Alan Mehta who Came to us from the University of Texas Alan's been here now Three years three years With his wife who co-lead our experimental therapeutics program and we'll talk to us about phase one trials in kidney cancer Thank you. Good afternoon It's a great pleasure and an honor to be here and giving a talk to Cancer survivor is always very special and very dear to my heart So we're going to talk about how to develop better cancer therapies introduction to phase one clinical trials and personalized medicine So I'm going to start with some numbers some mind-boggling numbers They are almost one and a half million new cases of cancer in the United States every year and more than half a million cancer related deaths The life type of ability of developing cancer is one in two in men and one in three in women And it's as estimated that about a quarter of our current population will die of cancer Cancer is now the number one killer of Americans under 85 on the bright side. They're also 10 million cancer survivor in the United States such as you and that is Related mainly to early detection and better treatments So why do we need clinical trials? We need clinical trials because obviously we don't cure all cancers yet And we need more efficient therapies We also need less toxic therapies that will improve our quality of life for the patients treated with for cancer And we also need to better match the patients with the optimal treatment, which is called personalized medicine Just remember the clinical trials is the only way to rationally develop new drugs and to bring new drugs to the patients to the market So how do you bring a new drug to the market to the patients? It's a step-wise and long process It takes about 10 to 20 years from research to bring a drug to the market And it's also very expensive one to two billion dollars to bring just one drug It starts here. Oh sorry It starts here in the lab when you discover a new promising agent And then you have to do long testing in the lab in cell lines and animals And if this drug looks promising then you go to the FDA and you have an Investigational new drug application, which allows you to start testing the drug in humans And if you talk about drug discovery you have here the drug discovery funnel that shows that it takes to test about 20,000 compounds to only bring one drug to the market So it's very discouraging and you have to go to this funnel in order to develop a cancer therapy Then once you identify this drug and you have the approval from the FDA to test it in patients It goes to the clinical testing and the clinical testing is also stepwise It goes to several phases the phase one clinical trials which ask the question is this drug safe Is it appropriate to use in humans the phase two trials as the question does this drug work? Is it good for a certain type of cancer and the phase three trials as the question? Is this drug better than our standard of care the treatment that we already have and then If all these questions have been answered it's a great drug Then you have the registration approval, but you're still not done You still have to conduct the phase four studies, which are the post-marketing trials We try to see that is there anything that we have missed while we treated this You know few hundreds of patients on these clinical trials is any signal that we we have missed So remember the drug discovery funnel after the drug discovery funnel comes a drug development funnel So when you enter the clinical trials not all the drugs make it to the market And it's estimated that actually one in 16 drugs that enter clinical trials. It's approved So it's a very very high attrition Rates in the clinical testing and we have to do a much better job here So let's start with the phase one clinical trials. What are the phase one clinical trials? So these are the first in human trials of critical step in developing any drug and because they are so sensitive And so critical are only done in a few centers 1 2 3 centers with a slow and very cautious accrual They typically accrue 15 to 50 patients and they integrate extensive research studies The main question that these trials are trying to answer is is this drug safe and appropriate for human use? The patient population that is enrolled in phase one clinical trials has to have a confirmed diagnosis of refractory cancer For which no effective therapy exists They are awfully heavily treated because they have to have exhausted all the available treatments and Typically they enroll various tumor types in a phase one clinical trial You generally enroll all type of cancers, but more recently There are phase one clinical trials that are disease oriented in a certain tumor type based on a specific target For example at Posada's talked about this hip to alpha Which is a target that is mainly expressed in kidney cancer and therefore it makes sense to try a phase one study only for patients with kidney cancer in this indication and These patients have also to have normal liver kidney and bone marrow function And this is a conundrum because this is a patient that have a long history of cancer a long history of treatments And they still have to be in great shape have normal liver kidney bone marrow function And that's why a lot of patients unfortunately do not qualify for these trials The goals of phase one cancer trials are to determine the maximum tolerated dose and the Recommended dose for further clinical testing, which is the dose that is safe and with a high probability of being also active And they also try to define the drug safety the toxicity profile the side effects and how to deal with them There are some secondary goals Which is how the treatment affects the human body? It's called the pharmacology of the drug and these are two words here the pharmacokinetics and pharmacodynamics The pharmacokinetics means the analysis of the drug absorption distribution and metabolis in other words What the body does to the drug and then the other aspect of this is the pharmacodynamic? That means what the drug does to the body the relationship between the drug dose behavior and the clinical effects One of the secondary goals of the phase one clinical trials is to document any efficacy that might occur Because safety is clearly very important But as cancer doctors we want to see whether this drug helps our patients is any signal that this drug is helpful and Very interestingly all the approved drugs that we have today for cancer have demonstrated at least one response in a phase one clinical trial and this response is also help orient the next steps the phase 2 trial because if you see a response Let's say in a patient with kidney cancer Obviously we're gonna go and do an exploration in more patients kidney cancer to see how robust that effect is Very briefly about phase 2 clinical trials These are the first time in a certain disease kidney cancer lung cancer prostate cancer and the question They are trying to answer is the drug efficacy in a certain tumor type. Does it work in kidney cancer? Does it work in lung cancer as a difference to the phase one studies? There's a multi-center and rapidly enrolling clinical trials They are usually completed within very few months and they typically enroll about 50 to a hundred patients The patient population for these trials also has to have a confirmed diagnosis of a cancer But with a limited number of prior therapies most often second or third line of therapy And they also have to have relatively normal liver kidney and bone marrow function tests and most importantly They have to have measurable disease and why do they have to have measurable disease is because we are trying to see What's the tumor response? We assess the tumor response to this treatment how the treatment impacts on the tumor volume? And we can achieve what we call a complete remission a complete response Which is a disappearance of all tumors, which is the ideal situation and we all celebrate when this happens We can achieve a partial response, which is a good reduction the tumor size, but at least 30% Unfortunately a lot of patients have progressive disease Which is a 20% increase of the tumor burden and everything in between is considered to be stable disease neither increase nor decrease most importantly we are trying to determine the duration of response because what we want to see is a robust control of the cancer and I Always teach my students if I have to choose between a partial remission that last two months and a stable disease that last two years I'll always take the stable disease So the duration of response is just as important as a tumor shrinkage and finally of course overall survival because that's what we Ultimately want to see want to see our patients living longer Just one slide about phase three clinical trials These are large randomized trials which compare the treatment under study with the best available therapy and the question that's asked is Is this better that what we've already have? So the patients are generally assigned by chance to one of the treatments and this is something that they never like but Unfortunately, that's the only way that we've been able to develop these drugs and these are large and expensive studies sometimes they enroll more than 1,000 patients for these trials and Surprisingly a lot of drugs fail at this stage about one in two drugs that arrives at this stage after all the research That has been put into fails at this stage So the major end points that FDA wants to see with his face this trial is survival They want to see that these drugs can make our patients live longer and Finally as I said even when you approve a drug you are still not done with the research We are doing this phase four studies after drug approval and marketing Trying to see if we miss something because we have treated a few hundreds or a few thousands of patients But sometimes there are side effects that happen in only 1% of the patients or less And we still have to try to identify these problems and to deal with them And this is what we're doing it here at Samuel Ocean comprehensive cancer Institute clinical trials are a priority because this is the way to offer cutting-edge treatments to our patients and We are offering phase one studies for patients who have received every reasonable standard of care We offered phase two studies for patients with certain tumor types where we know that progress is needed And we often phase three studies for the most promising drugs which could become the new treatments for tomorrow We also do translational studies and translation studies means that we are going back from the patient to the laboratory To better understand the side effects and the mechanism of action of these drugs and how to improve in the way we use them Now going back to renal cancer in 2005 the state-of-the-art Treatment for advanced renal cancer included two drugs only two drugs available in 2005 Interlucent two and interferon alpha and there was clearly a huge need for developing new and more efficacious treatments and then The targeted therapy revolution happened in renal cell cancer and it all started with some phase one studies This phase one studies with these drugs with barbarian names Bay for three nine zero zero six SU one one two four eight CCI seven seven nine They all have a common thread all these phase one studies showed some responses in patients with renal cell carcinoma as you can see here and this is something that was not seen before renal cell carcinoma was not always the refractory to all the treatments that we had and These drugs became thereafter Saurafenib Sunitinib temsir olimus drugs that we've all heard about and some of you have received already that had marked this targeted therapy revolution in renal cell carcinoma This is a slide that I borrowed from dr. Figlin And this shows the timeline of the approval of these drugs and the timeline of this target therapy revolution in renal cancer And as you can see here from 82 when the first responses with interleukin interferon were seen until 2004 Not much happened only one drug approved interleukin high dose But a lot of research a lot of research that allow us to understand how kidney cancer works and this research that was done here led to this revolution in just a few years from 2005 to 2010 all these drugs that got approved Temsir olimus everolimus pasopanib saurafenib sunitinib etc And we have now a rich armamentarium for the treatment of the kidney cancer cancer patients And yes, they do much better and they live much longer than they used 10 to 15 years ago Now remember all this started with phase one studies and In continuing this tradition we have here phase one studies for renal cell carcinoma And these are the four studies that i'm going to briefly talk about the phase one to trial of trc 105 and accytinib the pi is dr. Ed Posadas the phase one trial of pt2385 Pi being dr. Figlin the phase one study of mln012h and sgncd70a pi dr. Monica Mita The first one is the phase one to trial of trc105 and accytinib Accytinib is a drug that you may heard about it's approved for the treatment of renal cancer It's an all inhibitor of some receptor tyrosine kinases Such as vgfr1 2 and 3 these are implicated in angiogenesis as dr. Posada explained the formation of new blood vessels that are critical for the tumor growth and because of that they trigger tumor growth and cancer progression Now trc105 is an antibody targeting cd105 which is also an important antigenic target Which is very distinct from vgfr however and trc105 also inhibits angiogenesis tumor growth and metastasis in animal models And it nicely complements the activity of drugs that target vgfr In a phase one study the drug was well tolerated and caused a reduction of angiogenic biomarkers and tumor burden By targeting a known vgfr pathway this drug has the potential to complement the vgfr inhibitors And could represent a major advance in the cancer therapy The combination of this drug trc105 and accytinib is now currently under evaluation here at Cedars-Sinai The phase one part of the study has been accomplished and it showed that the drugs can be safely combined together And now the phase two part of the study is ongoing trying to see how much more active the combination is compared to accytinib alone, so stay tuned The next study is pt2305 which is a heft 2 alpha inhibitor So now we know after all that research I talked about for renal cancer that 90 percent of renal cancers Have a normal gene called vhl and this tumor suppressor gene being abnormal leads to accumulation of heft 2 alpha This heft 2 alpha and heft 1 alpha or hypoxia inducible factors are transcription factors that interfere with the dna And are implicated in cancer growth and resistance to chemotherapy and radiation therapy The drug pt2385 is a first-in-class and highly selective inhibitor of heft 2 alpha and it's orally administered It has demonstrated robust tumor regression and growth inhibition animals And it was safe and well tolerated in animals And now this first in human study with a drug was recently initiated at cedar sinai And the first two patients were already approached and will be enrolled in the next week or so Just a few words about a couple of other studies this study with mln 0128 This is a novel mTOR and pi3 kinase inhibitor if you want a super avarolimus The study in renal cancer Has been accomplished and is close to accrual and the final results are now awaited And this other trial with sg and cd70a in patients with cd positive malignancy cd70 was also identified to be an important marker for renal cancer And the study is now undergoing regulatory approval. We have to see it open in the next few weeks So stay tuned for this one as well The last part of my talk is going to be about personal medicine and how to better match each patient and its optimal treatment You've heard this morning that renal cancer is not one disease There are many many different types of renal cancer and they're all very different from a histologic microscopic standpoint But the biomarkers have advanced with technology And we evolved from the first hematoxiline aerozine stain Which allowed us to identify cancer cells within a normal tissue to immunohistochemistry Which allows us to identify this different type of renal cancers And now we are in the era of gene arrays And the gene arrays are if you want the molecular fingerprinting or the Genetical fingerprinting of a tumor And these gene arrays have been the nightmare of my fellowship I thought that i'm never going to be able to understand this is way too complicated way above my head When actually things are pretty simple On a gene array You have columns and each column is a patient sample or a tumor and you have rows and each rows is a gene And you have two color codes green, which means downregulated and red, which means over expression So on this gene array, you can see that for these patients here These genes are downregulated while these genes here are overactive Which is very different in these patients here who have a very different genetic profile And why is that important? It is important because molecular biology can allow us to diagnose and treat cancer more effectively And i'm going to give you an example in lung cancer, but this applies for any type of cancer including renal cancer This is a study that was done in a few hundreds of patients with one type of lung cancer All these patients had identical lung cancer from a microscopic standpoint However, when you do a gene array, you can see that there are at least three different types of cancers These patients here have a downregulation of this group of genes here and upregulation of this group of genes here This group of patients here have an upregulation of these genes here And the third group of patients have none of them And why is that important? These are some survival curves that show you how many patients are alive at 30, 40, 50, 60 months In this group of patients Almost all patients are alive at five years Which is very different with this group of patients where only half of the patients are alive at five years And very different with this group of patients where almost all patients are dead After just a couple of years. So clearly these are three distinct types of lung cancer Although they look identical on the microscope and this genetic profiling can separate these three groups And clearly we have to develop new therapies much better therapies for these two group of patients In order to achieve the same results as we have the the good group So this is the promise of tailoring multi-targeting therapies through personalized medicine So we hope that we're going to achieve that when you have a group of four patients Who have exactly the same type of cancer based on their genetic profiling You will be able to tailor the treatment and patient a will receive surgery and a target therapy Patient b will receive radiation therapy chemotherapy and another targeted therapy While patient c may only need a targeted therapy, etc, etc And also to choose which one of these target therapy is the most appropriate for each patient So this is a very famous painting by Rembrandt from the 1600s The anatomy lecture of dr. Nicholas Tulp And maybe dr. Tulp is showing his students a type of cancer based on the anatomic profile Where the cancer started and this is what we have been doing for 500 years But now we are moving in the genomic era and it's more important not where the cancer started But what the genetic profile of that cancer is Because what we have been doing for many many years When we had a group of patients and we have several treatment options patients were Recommended a certain treatment based on very rudimentary very primitive things such as a tumor size the number of lymph nodes and how it looked on the microscope And they were assigned to either surgery or radiation or active surveillance without knowing anything about their genetic profile What we hope to be able to do from now on based on the sophisticated genetic approach that we have available here at Cedars Is to match each patient with the best treatment And based on that molecular profile to tailor for each patient the most appropriate therapeutic approach Whether it's surgery radiation targeted therapy or maybe just active surveillance And we hope that this is going to be a much better way of treating cancer and to evolve towards personalized medicine My last slide The conclusion about clinical trials The national comprehensive cancer network Which is a federation of the best cancer centers in the united states has the motto that the best care of a cancer patient is within a clinical trial Unfortunately, only five percent of the cancer patients in this country are enrolled in clinical trials Keep in mind that without clinical trials will continue to practice yesterday medicine instead of the medicine of the future And that the first cure of patients with advanced cancer were seen in phase one clinical trials And therefore every clinical trials is a new hope for cancer patients Or if you want a new dawn such as this favorite painting of mine from onee and with this I am done and thank you for your attention