 Sujatha is going to talk briefly about clinical trials. It may not be pertinent specific to kidney cancer. You have heard a lot of information, but one of the idea is we think clinical trials is such a valuable part of what we all do. And we just wanted to talk a little bit about what these are so that you get some comfort level. So again, thank you Sujatha for doing this. Good morning, everybody. So like Sandy just said, let me start off by just getting a show of hands. How many of you have ever participated in a clinical trial? So few. I can count four. How many of you are currently in a clinical trial? Two, three. How many of you have thought but then not participated in a trial? One. Wait, we all understand when you get diagnosed with cancer, it's one of the most confusing times in your life. You go to your doctor, medical language, here's your treatment option. Hey, I also have a clinical trial for you. So I know going through that decision tree, like you've already seen surgery, chemotherapy, do I wait, do I go on a drug now? So it's very confusing. And one of the options for every cancer or actually all the chronic diseases now is a clinical trial. So the aims that I set forth when I prepared this talk for you guys is just to talk about the basics of clinical trials, just to introduce you guys to what the concepts are, give you a little behind the scenes of what happens at our end when we start planning a clinical trial. And I actually want this talk to stay with you when you go into your doctor's office and this word is mentioned again and you're like, OK, I heard that talk. I know what you've done and I know what questions I need to think about and ask you now. So that's my primary aim for this. So it's going to be a very non-medical talk, if you will. I also want to introduce you to the resources that you can look up. The internet is loaded with information and we can just help you direct you to the right websites, if you will. And then just talk about the trials in RCC that are available at Stanford right now. I'm not going to discuss the results of any trials, but just introduce you to what we have ongoing here. So what is a clinical trial? So it's a research question and it can be anything. It can be just getting x-rays every six months, improve the detection of lung cancer. It can be if I walk up the stairs, that does help my cancer. It can be, it's better for my cancer. So it's a research question. And what a doctor or a researcher is trying to do is to tell, if I give you this intervention, is that going to alter the course of your disease and is that going to slow or stop the disease? So that's the basic premise behind any clinical trial that's done. And I said interventions and like I mentioned, it can be anything. It can be a diagnostic test. It could be a PET scan, a CT scan, a blood test. It could be a vitamin. It could be an exercise regimen. It could be a lifestyle change. And then again, it can be surgery, radiation, chemotherapy as interventions that are offered to you when you participate in a clinical trial. So what goes on behind the scenes before we plan on a clinical trial? So researchers, doctors, we see patients every day and we keep thinking of how can I improve the outcome? What can I do differently? So a lot of the times, a lot of pre-clinical studies are done. That comes up with the biological rationale behind the question we're trying to ask. So a lot of the times we have a lot of testing done in cell cultures and lab animals from which we get data and then we say, this is a biological pathway. I have an intervention. I'd like to test it in humans. So a lot of this pre-clinical testing is done, published, reproduced, replicated. And for us to give us a sound base before we actually propose a clinical trial. When we come up with a drug, the US Food and Drug Administration has to approve its testing in humans. No drug is ever introduced. Even a prior approved drug, if it say, I'm making this up, say accident today is being used for kidney cancer, tomorrow I say I'm gonna use it for breast cancer. So even if a drug has been in the market but I'm going to use it for a different indication, I have to get the blessing of the US FDA to do it. Because the foremost thing in clinical trials is safety. And so that's what we call the IND. We always file for an IND before we start any clinical trial. And also when you're planning a trial, the one thing we all do is write a standard operating procedure, a standard operating manual, it's called a protocol. It'll describe our rationale, how we're going to test this in volunteers, what tests we're going to do, how often we're going to do it, how we're gonna monitor you for safety. And while we do that, the first thing that comes into mind is ethics. Is it appropriate for me to test it in volunteers? And so that is a question, that's answered not by the researchers, but we come up with a panel of people that includes clinicians, researchers, and even people from the public that volunteer to serve on these committees, that actually determine the appropriateness of giving this intervention out to the public. So we write the protocol, but an external body sits and looks at it, looks at the ethics of it, looks at the safety of it, and then says, yes, I think your plan is good, I think you should all go ahead and offer this to other people. This board, I'm sorry, this is called the institutional review board. Many of you might have heard this term, but this is the body that actually is in every institution that actually any hospital, any academic center will have an IRB that goes over all these protocols and it will appropriately flag questions and say, have you thought about this? Have you thought about how this could harm your patient or not? And we are liable to respond back to them and say, this is my plan, this is how I'll do this. So once we've written our manual, once we've got everything approved by our IRB, we go ahead and start our trial. Now there are different phases of a trial. I talked to you briefly about what a preclinical study is. Say I came up with a drug X and this is the first time I'm going to give it to humans. I don't know what dose to give you. I don't know if it's five milligrams or 10 milligrams. We've done preclinical lab work in mice, monkeys, and we come up with a dose and we say, okay, this is the safest dose that a primate tolerated and we're going to give it to the next primate and let's start with the lowest dose. So when we do a phase one clinical trial, our main objective is to find the safest dose that can be tolerated by human volunteers. The secondary objective maybe, is this doing anything to the cancer or to any other disease that it's being tested on but the primary thing is going to be safety and finding the right dose. So that's a phase one clinical trial. Few number of people and we're just testing it to see what the safe dose is. Once we know, okay, 10 milligrams of drug X actually was safe, did not cause a lot of side effects, then we go on to a phase two trial and now my aim is going to be different. Now my aim is actually going to be, yes, I'm going to look at the side effects of this dose but I'm also going to look at how effective it is in your disease. So this time we choose a more robust population. We're going to test the effectiveness of this treatment and hopefully all these people have the same kind of cancer to begin with, ovarian, breast, kidney, or you know, heart disease, Alzheimer's disease, high blood pressure, anything. So we start them with treatment with a dose that we've identified and then we monitor them for side effects and then we also monitor and see what it does to their disease. And once we complete the phase two, we then compare. Now this goal can be predetermined before we start the study and here's when all the PFS and OS and all those numbers come in and we're going to compare and see. So I have drug X for kidney cancer, Pesopinib did this, what did drug X do? And that's how I compare both of them and see what is better. Then we move on to a phase three clinical trial. If a phase two successful in telling us that a drug is actually effective for a particular condition, we go on to a phase three. Phase three is again a bigger population, one particular disease and here we usually have a comparison arm because that's what's going to tell us if you're standard treatment that's currently existing for conditions better or my new interventions better. So that's a phase three trial and it's in a larger group of patients and has a longer follow up. I'm going to go to this slide before I come on to that. So that's the timeline that we've talked about. Here's basic research, drug discovery, preclinical studies, phase one, two, three, FDA review and one drug approved. From here to here, the average timeline is 10 years. But now it's shrinking and it's all thanks to patients who participate in trials. The trials are becoming larger, we're able to accrue more patients. It's come down to five in some situations but on average this is a 10 year timeline. Phase four trials are done after the drug is approved and here we ask more questions. Okay, drug X work for kidney cancer, can I give it to patients with bladder cancer? And even in kidney cancer, the patients have been taking this for five to 10 years. What are they doing now? Did their cancer come back or what side effects did they have? So those are the questions answered in phase four clinical trials. So this is just the behind the scenes for you guys. What happens, how we plan, how we conduct. This is a very great website that I found actually when I was browsing the internet and had great questions. It talked in a very simple language and explained everything. I just wanted to put it up there. It will be in the end of my slide set too. So in this website, it pointed me to good patient questions and so I wanted to talk about, so when you guys go and see the doctor and you're offered a clinical trial, you should ask yourself, why should I participate in a trial? So what benefits do you get from participating in a trial? Remember, I told you it takes a decade. So you have access to the new research treatments before they're widely available. So you get a treatment on the clinical trial to date, might not be publicly available for three to five years down the line. So that's a great advantage of being on a trial. You will receive very careful medical attention from the research team when you're in a clinical trial. It's not just you and your doctor and perhaps a nurse, but you also have a clinical team working with you that is monitoring you, asking you extra questions, writing down everything you have because we're trying to learn from you what the drug does to you. So you're looked at really very closely almost as if you're put in a microscope. So you get a lot of very, very close follow-up and attention. And of course, you're helping the community in general by participating in medical research. Remember for kidney cancer, the last decade would not have been so notable if it wasn't for clinical trials. So what are the risks? Giving you a new treatment could cause some side effects that we don't know about yet. And we are learning together, so that's a concern inside risk that you have. Again, taking this drug may actually not help your condition and we don't know that. It's something we're trying to learn. Going on experimental treatments sometimes also means more doctors visits, more blood tests, more scans. And so, and it requires a lot of time from your end. You have to take off work, travel to your doctor's office. So it requires a lot of time commitment and lifestyle changes. So what do you need to know? So, okay, you're considering going on a clinical trial. You've heard about it. What do you need to know? You need to know what is the science? So I think in this day and age when we have cancer, we all go back home. We browse the internet, we read articles. We know there's a biological pathway or some biological mechanism to your disease or your cancer. So you need to know where does this drug come in? We all know about targeted therapies and such. Where does this drug come in the spectrum of treatment options that I have? How is it actually biologically affecting my disease? You also need to know about the protocol. This is the operating manual that your doctor wrote. You're not gonna see this, but you need to know what goes in it. In the protocol, we'll talk about who is eligible to participate. We screen patients very, very closely. We define things like, you know, you have to have no other chronic medical conditions that may actually harm your or affect your participation. You have to have good kidney function, good liver function. Some studies will say you can't have any active disease in your brain or brain metastases. Some studies or actually most studies will specify you have to be in really good cardiac health. So we go through all of that when we try to enroll patients in the study. The protocol also tells us about the test procedures, medications and dosages. So we will go through in detail about what medications you're taking. Are they going to interact with my study medication? What tests are you going to do? How often are you going to do it? How long will you be on the study? How is the investigator monitoring your disease and what are the expected effects and outcomes? So all this is in the protocol. This is a document that you don't see, but this is the document that you see. It's called the informed consent. It actually, Denise, correct me if I'm wrong, but almost a 20-page document that's given to you, 20-plus pages of all this information in the protocol condensed into this document that is given to you to read. And remember participation is voluntary. You can read, decide to participate and then decide, no, this is not for me. It's completely voluntary. What the informed consent does is it tells you about all what I talked about, the biological rationale, how we're going to do the study, what your expected side effects are going to be, how often you need to come in, what tests we're going to do, and how long we're going to treat you. So usually when you're in a clinical trial, we treat you as long as you want to be treated, as long as you don't have any unexpected or significant side effects, and as long as the drug is working for you. So those are the three scenarios where you are. So you're given this informed consent, you're encouraged to read it again, again and again, highlight your questions, write down your questions, ask a lot of questions. Believe me, we have to document the fact that we ask you to ask questions and we answer all of them, and that has to be an important process that happens between the doctor and the patient before you sign this. And only once you sign this is when the next step begins, which is we then start talking to you about, you know, let's get this test done, let's bring you in on this day. So none of it, no procedures are ever done without your consent. So this is a very key document that you all should be aware of as a part of a clinical trial. So what questions do you go in and ask your doctor? So what is the purpose of the study? I have kidney cancer, you're going to give me 10 milligrams of drug X. What is the purpose, what are you trying to achieve? So the doctor may say I'm trying to make your tumor not grow anymore, or I'm trying to shrink it, or I might just be trying to see if your quality of life gets better. Do you think it'll be effective? In other words, you're also asking, is this the right option for me? Being on this trial, do you think I should really take drug X rather than effinitor? How will you monitor me for safety? So this comes in, how do I reach out to you if I have something in the middle of the night? What symptoms am I supposed to look out for? Who do I call? And what tests are you going to see to make sure my heart is okay during this, my diabetes is okay during this, my blood pressure is controlled during this? How will you monitor my disease? You're monitoring me for safety, but then there's my cancer too. How are you going to look at that? How often are you going to do imaging tests to see if my disease is responding to this treatment? And how long will I be treated? Like I said before, as long as you want to, as long as you don't have bad side effects, and as long as the drug works for you. And what are my responsibilities? This means, what am I responsible for? I am responsible for coming to every doctor's visit. I'm responsible for doing the tests that you tell me are part of the study. I am responsible for telling you all the symptoms that I experienced during this treatment because we're finding out about this drug together. What are the possible short-term side effects? What are the possible long-term side effects? What are my other options? I don't go on a trial. What else can I do? Who will be in charge of a medical care? And now a lot of times people from the community come into Stanford because we have a trial here. And so it's confusing. So I had Dr. Jones in Walnut Creek who was my oncologist, but I'm with you on the trial. Who's in charge of my trial? As long as you're on a trial, the investigator doing the trial takes care of you, but you always have a relationship with your ongoing primary oncologist, and that's important for all of you to know. How will it affect my daily life? Am I going to be able to go to work? Should I take time off of work? Does somebody need to drive me into clinic? Does, do I have to apply for short-term disability? So on and so forth. And important, do I have to pay? So a lot of the times the trials are designed in such a way that a lot of treatments, tests and procedures will be standard of care. And when we say that, it means your insurance covers for it. Whatever the insurance doesn't cover, the company, the pharmaceutical company or the sponsor will cover for it. But you need to ask this question, how is this going to affect my finances? Am I going to be paying more? So on and so forth. There's some important terms. Every time we introduce clinical trials, some people really get, these are stopping points for people to stop and think. So what is a randomized study? So like I said, in phase three trials, we're always going to test the drug against the standard treatment options or sometimes a placebo, which I'll come to. And so what is a randomized study is that the study subject is randomly assigned to either your experimental drug X or you're going to get the standard of care treatment. So that is a randomized study. You will, a part of this is blinding. Sometimes you will not know what treatment you're receiving and that's scary for a lot of people. But here's why we do it. We do it to avoid bias because say you get Pizokinib, you know all about it, you get drug X, you know nothing about it. We need to randomize people to have, you know, study the biological effect of each drug. We need to blind people so that we don't bias the results of the study. So for example, if you knew what you were taking, you might come and say, you're absolutely right, my skin rash flared up or you're absolutely right, my diabetes got worse. So we don't want to bias the results. We actually want to know what impurity the drug is doing. So, and a lot of these times, in a lot of phase three studies, even the physician is blinded to the treatment option. So even I don't know what treatment you're assigned to and what drug you're receiving. So both of us are going to just look at the bird's eye view of it and we're not going to know what's going on there. And again, remember, this has gone through ethics. This has gone through planning. Nothing is going to be offered to volunteers that is going to be harmful. It's either going to be standard of care or the, you know, the drug in question, but the way that trial design happens is so that we don't bias the results. And placebo control studies. There's some studies where you will compare the drug with placebo. And like Sandy mentioned already, in this day and age, we have so many options. It's usually versus, go ahead. Time frame from the end of the study to getting back on. So that's a good question. And let me kind of back up and answer when you're in a randomized trial and their treatment arms. The way the studies designed also is that we keep comparing the results of both arms very periodically. And at any point in time, we notice a difference. Like one arm is doing much better. It is only ethical to stop study. And sometimes we cross over patients from that arm to the effective arm. Or if we see harm, we stop the study. Yes. Yeah. If it's working for you, you stay on the treatment and drug companies will allow for that. Say it was only for two years, but you've been on it, you've been doing great, your diseases are responding, you stay on it. So here's a slide. You're all very familiar, but this is our last great decade in kidney cancer. These are all the drugs that were approved, all because of patient participation, all because of clinical trials. We know so much more about how to treat. We have a lot of questions, but we know so much more about how to treat you guys because of these trials that were done in kidney cancer. These options have given us really effective options. We've been able to control the tumor growth. We've been, in some cases, even shrink tumors. And all this again happened because of patient participation. Where are we headed now with clinical trials in kidney cancer per se? There are a lot of pre-clinical studies again happening just to understand the biology of RCC. So there's researchers looking at this and trying to see what genomic pathways are underlying this disease and trying to come up with other suggestions and solutions about how to target them and treat us better. We are also clinically trying to identify biomarkers in patients, like, for example, who is the patient that's going to respond to an mTOR in an inhibitor better than a VEGF TKI or IL-2. So we're still trying to answer that question, which is the patient population that's going to benefit from treatment A versus treatment B. And you can call this personalized treatment and we're headed that way for sure. Like we've already looked at the slides that Sandy had, we're also trying to combine these agents and see if their efficacy is better. We're also trying to see when to give it to you after surgery, wait after surgery, so on and so forth. So we've already heard about those combinations too. And then immunotherapy. The immunotherapy in kidney cancer is the key player now. And how many of you have heard about this or not a lot, okay. So how our basic immune mechanism in the body works is that our body will not attack one of its own. It won't attack normal tissue because the tissues talk to the body and say, hey, I'm one of your own. Don't go ahead and attack me. And surprisingly cancer cells do that too. They tell immune system ways to evade their attack and say, no, I'm also one of you, don't attack me. So researchers have identified these communications that happen and they have come up with these drugs that break this communication. And that's what's the PD1 and the PDL1 blockade. This is just a communication between the tumor cell and the T cell. T cells are the key players of your immune system. So they've come up with drugs that break this communication. So what happens when the cancer cells stop saying, I'm not, I'm one of you, it says, I'm not one of you. So now the body taxes as a foreign particle starts attacking it. So this is like the basic mechanism how immunotherapy works. And the biggest player right now is Nevolumab. Like we talked about, data was just shown that it was effective, safely tolerated in patients with kidney cancer, clear cell. And their trials underway to get it approved. The phase three versus ever alignments that we talked about. And we're also testing Nevolumab and Ipilimumab. It is another immune checkpoint inhibitor in the first line setting. There are more. So Nevolumab is just one drug. There are other drugs that are also in clinical trials right now. The MK3475 and the MPDL drug. So what's available at Stanford? Actually, I thought I wouldn't go through this but I'm actually going to let you guys know what we have. We have a trial where we're looking at patients with early stage resected RCC and where it's a randomized study looking at giving them accident versus placebo. This is the trial we have here where in patients with metastatic RCC, first line treatment, sunitinib is standard of care. So we're comparing that to the combination of Nevolumab and Ipilimumab. In patients with advanced recurrent metastatic RCC, we are looking at the addition of this drug, delantercept and axitinib versus axitinib and placebo in this group of patients. We have a small trial which is looking at T-cell infusion in treating patients with metastatic RCC. We have some imaging studies. This is just one. I think three more that are looking at perfusion CTs or images, once you start a treatment, doing an early scan versus a later scan to see if the early scan actually is predictive of whether the TKI is working for you. And then we have a trial specific for papillary RCC subtype. We also have one for sarcomatite RCC. That's not up here. And this again is just imaging study that we have. Yes. I'll do. I'm not aware of that. And these are the resources I wanted you guys to kind of go back to or look up if you ever had a question. Clinicaltrials.gov, you all must have seen this. So this is the website where we all, whenever we run a clinical trial, we have to go on here and register our trial. It is actually good for you guys to go through because it will list all the inclusion and exclusion criteria that I talked to you about. So you and your doctor can actually go through there, look up a trial, see if you're eligible before you get a plane to get to go somewhere, go participate in a trial. This is cancer trial specific to Stanford. Kidneycancer.org, this organization's website. I think it had great clinical resources. It actually also lists all the active ongoing kidney cancer trials worldwide and even specifically in the United States. So that's good to look up. And then this was the clinical trial basics website that I referred to earlier. Doctor, this is all pretty much national ideas but are there any international resources? So clinicaltrials.gov has international trials. So you guys might be familiar with it. So NIH is here. So you know, more international sources are more also based on guidelines that come or are set forth. So like for United States, we have the NCCN or the National Comprehensive Cancer Network. We have ASCO, those are the bodies that kind of help us develop guidelines here. When you go on to Europe where treatment options and modalities may be different, ESMO is a good site to look up for patients. They have a patient specific website where they talk about all this. And I can take questions. Yes. All the hospitals follow the same safety procedures while following the clinical trials or should we weigh Stanford or Anthem or Kaiser or whatever? So that's a great question. And yes, so there are international guidelines about ethics in human research. And we also follow something called good clinical practices. So doctors and all our research stuff, we actually have to sit in a training and get certified before we actually participate in any trials. And so these are standard procedures, standard education materials available to everybody. So everybody has to go through this training. And you know, like I said, the IRB has to review all your protocols in the way you're conducting a trial and approve it. The IRB will also have interim audits to see how you're doing. And if there has been any safety concern in the trial, like somebody experienced a side effect, they're actually going to have you come down and sit with them, explain what happened and how, if we are going to modify anything to monitor the safety of our patients. Again, when a trial is done, it's not only the institution, but there are also external bodies that are looking over our shoulders and seeing what's going on. One more question. So when does FDA involvement come into picture? Like is it before phase one or is it after phase one? So again, good question. So again, phase three mostly because that's when the data starts to emerge about. So we have more data about the side effects of the drug by the time it's in phase three. And we also have a comparison now. So say we had treated ovarian cancer with a drug for the last 10 years and now suddenly there's a new treatment. Now we can actually compare the two. And that's when the FDA comes in and weighs in and says, yes, you're right, your data actually shows that you can make a difference and giving the new drug versus the what was standard of care for the last decade is actually better. So it's usually phase three. And some trials may show promise even in the earlier phases and sometimes they're given an accelerated designation or approval where it's fast tracked to the FDA where they will ask for more data or earlier data. And if it's a high impact disease where you know survival matters for patients, especially with any kind of cancer, FDA will do that. They'll say, give me more data, give it to me fast. Cause if I approve this quicker it can actually make an impact. So actually you can be anywhere, we have patients who, because we have a trial available, we have patients who come here, fly out here for treatment. You don't have to be here. Again, you don't have to have a Stanford doctor, your community doctor can refer you to Stanford and we can take care of you for the duration that you're in the trial. Unfortunately, if we have the trial, we can have you go back and have it with your doctor. You have to be here for the duration that you're participating in the trial. Yes. What was the first direct? What is it? So fast track, like I showed in the set, so the FDA approval for a drug can take a year to two years, right? But if there's compelling data, which is showing that people are benefiting from it, it has been a safe treatment and we're actually improving survival and it's a high impact disease. For example, metastatic kidney disease or metastatic colon cancer where the faster it's publicly available, the faster it's going to save lives. At that time, people will push FDA and FDA will say, yes, let's give this a fast track designation where we are going to go through the review process even more quickly and get this drug out approved into the market quicker. All right, thank you.