 Okay, hi everybody. My name is Susan DeMo and I'm head of medical affairs at Caluthera Biosciences, and I really want to thank the kidney cancer association for inviting me to speak at this wonderful meeting. So I've been doing drug discovery in biotechnology industry for the last 20 years. At my previous company, I worked with the group to develop a new treatment option for patients with multiple myeloma. And now at Caluthera, we're a small company in California and we're hoping to bring new therapies to patients with renal cell carcinoma. But I'm really happy and grateful to be at this conference because I firmly believe that developing new treatment options really takes teamwork. It takes participation of multiple types of disciplines. It takes researchers, physicians, nurses, hospitals, biotechnology companies, pharmaceutical companies, but most importantly patients. So I'm really happy that the KCA has organized this conference that's really focused on patients. And I'm particularly excited because I'm a PhD unlike the other presenters who are mostly MDs. And that means that I've spent most of my life in the laboratory and the laboratory can be kind of a lonely place. I've spent my time looking through microscopes at cancer cells in the dish and trying to understand what's making them grow and how can we find new ways to stop them from growing. But I know that cancer is not just the cells in the dish and that patients have a lot of information about cancer. And I'm really passionate about finding ways to increase interactions between researchers like myself and patients. So I really appreciate the KCA for hosting this conference. So today I'm going to talk to you about developing new therapies and how that's accomplished and really focus on the therapeutic and really focus on clinical trial process. So I will try to advance this here. So I'm going to start with the basics and just describe. I know we've talked a lot about clinical trials. We'll take a step back and let's really look and understand what is a clinical trial. I'll spend a few minutes trying to describe like how do we find the new drugs that we use to test in clinical trials and why do we have clinical trials and what happens in a clinical trial. And then I'll focus on what's in it for me. Why might a patient think about enrolling on a clinical trial or why they might not want to enroll on a clinical trial. And we'll cover some of the benefits of participating and some of the reasons why you might not want to participate. But I'm really here to say that more research leads to better treatments and we need to keep going. So in the last decade there's been a lot of advances for the treatment of patients with renal cell carcinoma and that some of those therapies are shown here and some of them have been talked about already. Oh here we go. Some of them have been talked about already at TET's meeting and I'm sure we'll hear more about them this afternoon. So all of these new agents and their activity have been discovered and characterized through the clinical trial testing process. So I'm going to go through and talk about that process with the emphasis on how important it is and why we need to keep going to find better treatments. So what is a clinical trial? Well very basically clinical trial is a research investigation in which people volunteer to test new treatments or new interventions. And it's really a sort of the modern model of patient care which is called evidence based medicine where we really use scientific rigorous process to determine whether a new treatment really is more effective than the current treatments that are used. In other words it's called standard of care. And it's really the best way to try and figure out how to treat patients. Oops. But I'll say a few words about how we actually find cancer drugs, the drugs that we then put into clinical trials. And this slide shows some three different mechanisms how new drugs are found. The first when drugs can be found through a random screening process where compounds from a variety of sources are brought into the laboratory and tested to see if they can block cancer cells from growing in a dish. And an example of that is the chemotherapy pachytoxal or taxal that you may have heard of. So taxal was found out of an effort in the 1950s that the National Cancer Institute had for screening compounds that they found in nature, mostly from plants. So pachytoxal was isolated from the bark of the specific U tree which is found in the Pacific Northwest. Scientists isolated the compound, tested it in cancer cells in the laboratory, found that it could block the tumor cells from growing and then they tested it in clinical trials and found that it brought benefit to some patients. And interestingly nature can make very complicated compounds and for years those clinical trials were conducted with the compound isolated from the bark of this tree. It was only until the 1990s that some smart chemist figured out how to make pachytoxal in the laboratory and that's how it's generated today. But there are other ways to find new drugs. Biologists can spend their time trying to understand what are the mechanisms that the tumors are using to propagate themselves and to grow and to survive. And so Dr. Hus talked on this particular pathway where the VEGF inhibitors are designed to stop tumors from being able to promote the vascularization. So increased blood vessels going into the tumors are good for a tumor because it allows more nutrients and oxygen to come in. And biologists discovered that this VEGF pathway is what's maintaining that. And then they went on to work with chemists and develop those compounds that could specifically target those VEGF pathways and block that process and then kill the tumor and hopefully shrink the tumor. Similarly biologists can use their mechanisms to study tumors to see if they can find ways that the tumors trick the immune system and hide from those. And it was out of that studying in the laboratory that the new immune therapies that we've heard about already today and I'm sure we'll hear more were discovered. These inhibitors will target pathways that allow tumors to hide and not be found or seen by the immune system. So you send in these therapies they block that and it unmasks the tumors and allows the immune system to go in and target them. Okay so once you have a cancer drug how do you find out you think it works in the laboratory but how do you find out if it works in patients. And then how do you test that and then how do you get it actually to be approved and then be able to use in a larger population. Well that process can take a long time from 10 to 15 years and it can cost a lot of money from a half to a billion dollars. And it's outlined here where I've already sort of talked about this process of testing in the laboratory to see if the compounds are able to stop cancer growth in the laboratory. And it can take three to six years and take testing of tens of thousand compounds where you whittle it down and try to find the best compounds to take forward into the clinic that have the most chance of being an active new therapy. Those compounds are then brought into clinical trials and I'll talk more about this on subsequent sides of the nature of clinical trials. But this clinical trial testing can take between six and seven years and can be tested in thousands of patients. And once these clinical trials are conducted all the data is submitted to the FDA the Food and Drug Administration. And they review the data and they will determine whether this new drug really has benefit above the current standard of therapy. And is it safe and does it beneficial for patients. And if they deem that yes it is they'll approve this agent and then it becomes widely available to cancer patients. So how did this process of testing compounds in clinical trials come about. Well it started in 1937 with what's called the elixir sulfonamide incident. At that time there was no safety testing required for new drugs. And a pharmaceutical company in Tennessee was trying to make a better way to deliver this sulfonamide which is an antibiotic. And a chemist found that he could solubilize it in this compound called diethylene glycol and mix it with cherry flavor which made it more palatable for people to take. They then marketed this drug but sadly hundreds of people died. Many of them were children because diethylene glycol unbeknownst to the chemist who made that formulation was actually toxic and those patients died. So out of the outrage that came from that incident President Roosevelt in 1938 signed the federal food drug and cosmetic act which required that new drugs be tested for safety and that data be sent to the FDA. A good example of the FDA and what it's done to protect all of us what happened in 1960. Well it happens all the time but a nice example is in 1960 when a medical officer named Francis Kelsey was working at the time when they were trying to get thalidomide approved for use in the United States. And you may remember that thalidomide was being used by being taken by women in Europe and in Africa to help them with morning sickness. And there was a big push to the FDA to try to get thalidomide into the United States to be given to pregnant women but Francis Kelsey blocked it. She looked at all the data that was associated with that molecule and said there's not enough data and I don't think it's safe and she blocked it from coming in. And of course sadly I'm sure you remember that the babies that were born from those mothers who were taking thalidomide had birth defects. And for her efforts to really keep us safe she won the Presidential Service Award. She was only the second woman at that time to be given that honor. So in 1962 the Kiefer-Harris amendment gave the FDA control over the experimental process of testing new drugs in people. And that led to this four phases of clinical studies that we use today and I'll describe on the next slide. So after you do all of that preclinical testing that I spoke about and generate the data that shows that the drug might have activity and all the safety that's associated with the drug from testing in both in vitro tests like in the test tube or in vivo tests in animal studies. All that data is compiled in what's called an investigational new drug application that has to be submitted to the FDA. The FDA reviews all of that data and if they deem that it makes sense to take the drug and test it in humans and it's safe enough to test in humans then they will allow it to enter into the first phase, this phase one study. It's called the first in human studies. It's usually in a small number of patients, 15 to 80 patients actually it could be in healthy volunteers or in patient volunteers. The main purpose of this phase one study is to understand what the safety of this molecule is. What are its side effects? What's the best route of administration and what's the best dose to be administered to achieve the fact that you're trying to achieve? If the drug is deemed safe enough from this first phase it will get passed to what's called a phase two study. This is a bit larger between a dozen and 300 patients and it happens in the, it's tested in the patients with the disease of interest. You can get further information out of this larger study about the side effects and also learn more about the safety issues. You can also learn something about potentially the activity or the efficacy of this new compound. But to really understand its activity the compound has to be tested in a phase three study. This is much larger anywhere between 300 or 100 to 1000 of patients that are randomly assigned to treatment arms. And Dr. Haas talked about some of these types of studies earlier. In the different treatment arms they test the comparison of the new therapy in comparison to the current standard of care. These studies are designed to have full approval from the FDA. So the results as I mentioned earlier of these studies are submitted to the FDA. And if the data is compelling the FDA will approve it and make it available for the general population. After that the phase four studies can be conducted. It's not mandatory but they can be conducted. These again can be eight thousands of patients. And the idea is to kind of continue to try to understand the activity of the drug in the larger population looking at side effects, risks and benefits and with treatments over a longer time. So what kind of questions can be asked in a clinical trial? So we've already talked about finding the safe dose, finding how the best route of administration for the drug, what are the side effects. But also you can test in a clinical trial whether the new treatment has better quality of life with fewer side effects. You can also ask whether the new treatment can shrink tumors or slow its growth or prevent the tumors from spreading to different places in the body. And you can also ask whether the new treatment will help prevent the cancer from coming back after the treatment is finished. But the ultimate question is does the new treatment help patients with cancer live longer? So we talked a little bit about a randomized trial earlier. So I thought I would explain what a randomized trial is. Some phase two but all phase three trials are randomized in which patients are assigned to groups that receive different treatments that are being compared to each other. There's an investigational group that receives the treatment being tested and there's a control group that receives the standard therapy. And I want to iterate here, if there is a standard therapy available for the patients that are enrolled on this trial then they will receive that. They won't receive a placebo, they'll receive the standard of care for that treatment. The FDA won't allow you to have a placebo in that situation where there is a standard of care. So a computer is used to assign the patients to the different groups. It's to randomly assign the patients to the different groups. And some randomized trials are blinded so that neither the doctor or the patient knows what they're getting or has control of what they're getting. And this is really important to reduce the chance of bias on the study. So what's it like to participate in a clinical trial? Well, a clinical trial starts with a protocol. If you've been in a clinical trial or you know someone who's been in a clinical trial you may have heard them say, I'm on a protocol. Well, what is the protocol? A protocol is a written document that has a plan of care for the patients on the clinical trial. It identifies the principal investigator who's running the study which is typically a doctor. It'll talk about the reasons for the study. What's the supportive data that suggests that this new treatment should be tested in patients? It'll outline the criteria of who can join this study, who is eligible. That's an eligibility criteria it's called and who cannot join the study which is called an exclusion criteria. It'll talk about the number of people in the study, the different treatment that's being dosed, that's being administered, how it's being dosed and what will be being dosed in the route of administration. It'll also outline the testing that's going to occur at baseline while the patient's on the study and at follow-up. So what are the elements of an eligibility criteria? So what are the things to consider on whether or not a patient can enroll on a clinical trial? Well, sometimes it'll depend on whether the patient has a certain type or stage of cancer. And sometimes it'll depend on whether the patient had received any prior therapies or other therapies, whether they have or hadn't, it can just depend on what the trial is trying to achieve. It can also depend on whether there's a specific change in your tumor or whether there's a certain age group being tested or medical history or current health status. So it's important to point out that all of these eligibility are quite critical for the proper conduction of the clinical trial. While they might seem quite stringent, it's important that they be followed because the purpose of these is to help keep the patients who enroll on the trial safe and also to allow for there's a homogeneous group of patients so that when the data comes out, the investigator can make sense of it. Another component of a clinical trial is informed consent. So what is informed consent? It's the permission that's granted from a patient to a doctor for the treatment that they're being given with the knowledge of the possible risks and benefits. And actually informed consent is really an intrinsic part of medicine, but it's more formalized in a clinical trial. When you are asked to think about a clinical trial or want to consider a clinical trial, you'll be given what's called an informed consent form. This document contains the purpose of the study. It describes what's being studied, what is the new drug that's being tested. It'll describe the details of the study, what's the dosing, what are the tests that are going to be done. It'll also describe to you the possible risks or side effects and what are the potential benefits. It outlines the fact that this is a voluntary participation. You have the right to withdraw and the right to get a copy of the consent. I think it's important to know and remember that signing the document and providing the consent is not a contract. A patient can withdraw from the study at any time even if the study is not over. So who protects patients on a clinical trial? Who reviews these protocols and decides whether they're appropriate for these clinical trials to start and who's going to ensure that the patients are safe while they're on this clinical trial? Well, first of all, the FDA has to review the clinical trial. They review every protocol that's initiated. But then the hospitals where the clinical trials are open also have their own safeguards where they have panels of people who review the protocol and the informed consent forms. There can be a scientific review panel that occurs on all federally funded studies. It's a comprised of experts. They review the protocol to ensure that the protocol is based on sound science. And then what occurs on all trials because it's mandated by federal rules, there's what's called an institutional review board that's associated with the hospital or the institute. It's a diverse membership that includes at least one person outside of the hospital. They review the clinical trial protocol to make sure that it's safe, that it's fair, it protects patients' rights, and there's an appropriate balance between the risks of the new treatment and the questions being asked. And then while the trial is being conducted, there's what's called the Data Safety Monitoring Board. It's a part of all Phase 3 studies and it may be a part of some Phase 1 or Phase 2 studies. It's an independent group of statisticians, physicians, and other healthcare professionals that monitors the safety that's emerging from the study as it's ongoing. This Data Safety Monitoring Board actually has the power to stop a study if they feel that the safety events that are emerging are too risky and not worth carrying on. So what's it like to enroll on a clinical trial? What's the process? So first your physician will discuss with you whether the clinical trial might be right for you. You'll be provided that informed consent form that I spoke about. And if you agree to participate, you'll be screened to see if you fit the eligibility criteria. And if you do, you will be enrolled if you agree to participate. If the study is randomized, then you'll be assigned to a treatment arm. The study-specific procedures are administered by the clinical trial staff, typically a research nurse and the physicians involved in the trial. The treatments, the number of assessments, the visits to the hospital are all specific to each study and are described to you in the informed consent. Typically patients continue to see their usual health care providers while they're enrolled on a clinical study. So let's think about why patients may or may not want to participate in a clinical trial. So what's in it for me if I participate? So here's some reasons why a patient might want to enroll. It could be that they hope to receive better therapy or better care or breakthrough therapies as they're emerging. They could have an altruistic intent and they want to contribute to the scientific knowledge. Or it's that they trust their physician and their physician has recommended this clinical trial as the next course for them. Or they have limited options for effective standard of care therapies. So what are some of the reasons why a patient might not want to participate in a clinical trial? Well, there could be a fear of letting chance decide the therapy or fear of the side effects or that the new therapy is not as effective as a standard of care. Some patients just don't want to be a guinea pig. It could be that there's too many of the trials inconvenient. It requires too many visits to the hospital. It's too far, have to travel frequently. Or it could just be lack of awareness or information that not enough information is known by the patient about the clinical trial. The National Cancer Institute's published their view of the potential benefits and drawbacks of being on a clinical trial. One benefit is that you'll have access to new treatment when it's not available to patients that are outside the trial. When you're on the trial, the research team will watch you closely and it'll get very attentive care. And another benefit is if the treatment that study is more effective then you may get that treatment and be one of the first to get it. And as I said earlier, a benefit is the trial helps scientists learn about the treatment and may help people in the future. But what are the drawbacks? So the treatments aren't always as good or better than the standard of care and the new therapies may have worse or new side effects. The treatment may work for you but it might not work for others. And there could be potential increased travel or costs associated. But I do want to point out here that frequently when you're on a clinical trial they actually have ability to cover some of these costs. So you should ask actually if you're thinking about a clinical trial. So if you're thinking about a clinical trial how do you find out about them? Well the best place to start is with your doctor or other members of your health care team ask them about clinical trials that they think might be right for you. There are also a numerous number of websites that you can look at. A good place to look is your hospital itself. Frequently these hospitals will list the clinical trials that are open at that center. But the National Library of Medicine has a what's called clinicaltrials.gov which is a big warehouse compository of lots of clinical trials that are actually here in the United States and internationally. These are searchable and you can enter your diagnosis and find trials that are right for you. The National Cancer Institute may be right for you I should say. The National Cancer Institute also has lists of clinical trials and frequently pharmaceutical companies and biota companies will list the trials that they are sponsoring on their website so you can look there. And importantly cancer advocacy groups like the Cancer Association they have a really nice website that I hope you've visited that outlines clinical trials specifically for patients with kidney cancer. So in summary I hope that I convince you that clinical research is critical clinical research is critical to advanced medicine and that increasingly effective RCC therapies have been developed through this clinical trial process. But unfortunately only 3% across all cancers only 3% of patients participate in clinical trials and really that low participation really does impair the pace of progress and that includes in RCC. It should be noted that standard therapies and clinical trials are both viable options for RCC patients but the decision to be in a clinical trial or receive standard of care is individualized and there's really no right or wrong. So I thought I would end with a real world example of trying to develop a new therapy for treatments with for patients with RCC from the experience that we're having at Caluthera Biosciences. So Caluthera was founded in 2010 with 25 people and now we're still small, about 80 people but it's a mixture of scientists, chemists, biologists, pharmacologists, clinicians, clinical operations people and we're all working together to try to bring new therapies to patients. We decided to try and see if we could make new therapies to test that block the cancer's ability to get nutrients to survive and as shown in this schematic picture here you're probably aware that normal cells will eat glucose from the blood. They take glucose in, they use it to get energy and to make the building blocks that they need to stay alive. Well cancer cells also need glucose. They take up glucose and use it to get energy but a German scientist named Otto Warburg in 1928 was studying cancer cells in a dish and what he observes is that cancer cells are taking up glucose but they're using it differently. They're converting it to lactate which is kind of like what your muscles do when you're like physically exercising your muscles quite hard and so he observed that going on in tumor cells in the dish and what that means is that in some cancers they need to find other ways to get nutrients into them to help their processes to stay alive and some cancers will start taking up this amino acid, glutamine and in order to use glutamine they need this enzyme, glutaminase. So at Caluthera we decided to see if blocking glutaminase could starve tumors and cause them to shrink or die. So we made an inhibitor of glutaminase and tested in the laboratory to see what it would do to tumor cells and indeed we saw it could kill cells in the dish and we tested it in our animal models of tumors and showed that it could slow the growth of the tumors in these animals. So now we need to ask, we have activity in these pre-clinical laboratory models but in order to ask the question does the inhibiting glutaminase also shrink tumors in humans and can it be an improved therapy for patients? We need to run clinical trials and currently we're conducting two clinical trials in clear cell RCC patients. So with that I want to thank you and I want to say I want to hear from you. I said at the beginning of my presentation that I'm a research scientist and I really want to find ways to engage and interact with patients. So I'd love to hear either now or after this meeting and if you can't find me afterwards I've put my email address down here. I'd love to hear if you've participated in a clinical trial and why you chose to or why you chose not to and if you did what was your experience and other thoughts or opinions that you have. So thank you.