 Hi, I'm Kari Kinoski and this is Kidney Cancer News. This month, we'll have presentations from the experts in the treatment of renal cancers. But first, Bill Brough has a report on how grapefruit may boost a cancer drug. Drinking a glass of grapefruit juice a day could dramatically increase the effectiveness of cancer drugs. As reported in the mail online by Claire Bates, patients who combine the fruit with a specific anti-cancer drug receive the same benefit as they would from taking more than three times the dose of the medicine itself. University of Chicago researchers said the combination could help patients avoid side effects associated with high doses of the drug and reduce the cost of medication. In a study published in clinical cancer research, the team showed that patients who drank eight ounces of grapefruit daily increased their serolimus levels by 350 percent. Serolimus rapamycin is used to prevent rejection and organ transplantation, but it's also being tested as a treatment for certain tumors. No patients in the study had a complete response, but about 30 percent of the initial three trials had stable disease, meaning their cancers did not advance. One patient taking grapefruit juice had a partial response, that is significant tumor shrinkage that lasted for more than three years. Reporting from suburban Chicago, I'm Bill Brough. So this was his outline for the talk, and it wasn't so much on novel therapies. It was more about clinical trials, why they're important, talking about a little bit more about the different types of clinical trials, what's gone on in the past, which we've been well covered by others, particularly Dr. Yonash, but also some of the planned and current trials that are going on that should give us some information in the next year or two, mostly with a focus on phase two and three trials. And probably the most important question of the day, not just for people in this room but for people listening online, is why should you participate in clinical trials? What's in it for you? We've obviously talked about what's in it for the field, but what's in it for patients who might want to consider trial participation. So here's the definition of a clinical trial, it's a study conducted to look at both the safety and effectiveness of any health intervention, could be a drug, could be a device, could be a treatment protocol. They're designed based on certain ethical guidelines, which we follow very closely and we're monitored very closely by folks internally and externally, like the FDA and our IRB institutional review boards at all of our institutions. This is one of, this is a list, so I thought this was a pretty funny list that Dr. Bukowski came up with from a Persian physician on the ways to conduct clinical trials. This is from 1025 AD, so 1,000 years ago. And you can see a list of some things you want to think about before you're doing clinical trials. I don't know how many clinical trials were done 1,000 years ago. I thought the last one was the funniest. Number six, it talks about the experimentation must be done with the human body, which makes sense. For testing a drug on a lion or a horse might not prove anything about its effect on man. We talk a lot about morbidity and mortality to patients on clinical trials. I can't imagine being the investigator on any lion trial. It would probably be higher for the investigators and for the lions. But I'm glad we've made advances in the last 1,000 years. This is one of the more famous early medical intervention clinical trials. This was by British investigator James Lind in 1747. He was the first to show and prove that citrus fruits can cure scurvy. He did what was somewhat like a randomized trial as today, comparing the effects of various acidic substances such as vinegar, citrus fruits and cider, giving patients sailors with scurvy and essentially proving that giving oranges and lemons can improve, can cause recovery rapidly in patients with vitamin C deficiency. One of the founding fathers of our field of clinical investigation, but we've actually come a long way since then. As far as types of clinical trials, there can be classified in different ways. Some are just what are called observational, meaning we collect data that other researchers use to study patterns, study outcomes over a long period of time, for example, certain things like risks for heart disease and cancer, that sort of thing. What we focused on mostly for this meeting are interventional trials where we actually do something to patients usually with a device or a therapy and it's often compared to patients receiving either no treatment or commonly the standard or the old standard of care. And there can be many different purposes for clinical trials. Some of them are prevention and some of them are screening, which we haven't talked a lot about yet. And some are more active treatment trials or improving our way of diagnosing certain cancers. So there are many different types of trials. You often read a lot about different phases of clinical trials. This is sort of an important concept when you're trying to decide whether a trial is right for you, you often want to ask what phase is this trial. The reason that's important is each phase of clinical testing has a different goal. I'll focus on the ones in the middle here. Phase one often focuses on drug safety. So over the years, it's been about questions like what's the right dose of a drug? What's the right schedule for a drug? And traditionally, phase one trials have not really been great for patients because the main focus was what's the safest way to give this drug, not necessarily how effective the drug is. And they were often left for patients with fewer other options when others when everything had run out, you would consider a phase one trial. But nowadays, phase one trials are changing somewhat. Number one, they're not just open for anybody with any type of cancer. More often, they're open for patients with specific types of cancers because there's already some sense of why this drug that was looked interesting in the laboratory might be effective for a specific type of cancer. So we're getting a little bit more focused in that regard. We're also testing patients, for example, certain tumor characteristics before they go on a clinical trial. So even getting more detailed information than just what type of cancer they have, but what kind of tumor do they have? What kind of genetic changes are going on in that tumor? And most importantly, some phase one trials, once they get the safe dose, are then doing what are called dose expansions where they take groups of patients with a specific tumor type and treat them all at the same dose, which is essentially doing a phase two trial in what's called a phase one trial. It's a much smaller phase two trial. And in many ways, there are advantages in my admittedly biased opinion to being on that kind of a trial because you know you're getting the drug at that point. You know you're getting a drug that in many cases has shown some sense of safety and activity. And it's certainly something you should consider, not necessarily write off because your doctor says, I want to consider you for a phase one trial. Phase two trials are sort of the main focus there is effectiveness. How effective is a treatment? And they're usually focused on a single cancer type. And phase three trials, which you've heard a lot about, are more comparative trials, comparing something new to something that's old or standard. And for many years, the new was never really better than the old. But one of the things that we hope we've gotten across in this day is more recently, a lot of the new stuff has been better. And we often had a sense of it that it might be better before we got to confirming it in phase three trials. One of the uncomfortable things about phase three trials from a patient's point of view is the randomization that makes people very anxious. They don't, you lose a certain amount of control, both physician and patient over what you're going to receive. But so a lot of people will choose not to go on phase three trials because they're uncomfortable with that process. The way I like to look at it, and obviously not from a patient's perspective, is that even in the randomized trial, you get a 50% chance of trying a new agent earlier. And that may not be for you. It's obviously a very personal choice, but it's at least worth a discussion. It's worth a consideration as you go through your treatment. There often are trials after a drug becomes approved, like for example, expanded access trials, where they offer it to patients just to test further questions like safety, for example. So we talked a little bit about clinical trials so far. I wanna speak a little bit about caveats. We talked a little bit about randomized trials and how that can often throw people off, but it turns out it's the only real way of proving that a new treatment is effective. So as many flaws as a randomized trial might have from a patient's perspective, it is here to stay at least for the time being. We're still gonna be doing randomized trials. There's other concepts that are often also throw people off. One is whether a trial is blinded. That means that the researcher and the patient may not know what the patient is getting. And you might say, well, why is that? The reason that is is oftentimes you will make, if you know what someone is receiving, you might make judgments that bias the outcome and they wanna try to reduce that bias, both on the patient side and the physician side. But a lot of people don't like not knowing what they're getting. And the one that throws the most wrenches into this is the whole concept of a placebo as a control arm. And that unnerves a lot of people for good reason, but you are gonna be told if a placebo is involved, number one, for sure, upfront. And most importantly, now that we have effective drugs, placebo controls are less likely to be acceptable options. Meaning they're only acceptable if there's no standard treatment. So five and six years ago, when there was no few standard treatments for kidney cancer, we relied on placebos. But for the most part now, most of these new treatments are being compared to active treatment. So you're either getting active treatment A or active treatment B, comparing it to a new treatment. Going forward in kidney cancer, there'll probably be fewer and fewer placebo control trials. Here's a list, you've seen this before, of all the trials that have been done in the last 10 years. And I think the important thing about this is it's patient involvement that's made this progress possible. This is a look at eight or nine trials that have enrolled almost 4,000 patients. It's quite a long list of progress that can only be made by patients willing this to participate. So it's something to encourage people that you know if they're interested, you may communicate with online or through email to consider participation, because it's only through that participation do we make this progress. And we clearly have much more progress to go. So in summarizing our recent advances, we've been able to show that we can shrink tumors at up to 10, sometimes 50% of patients with these newly targeted agents that Dr. Jonas was talking about. We can certainly slow tumor growth, which leads to lengthening of survival. Dr. Hudson was talking about his patients are living longer. My patients are as well. They're living years longer than they used to in the past, but we're still not achieving enough remissions. And we need to work on agents that might give us a chance of remission or that benefit once the treatment stops. Obviously we talked about participation. We need to do that to improve outcomes. And hopefully in the future, we can see trials that better understand the biology of kidney cancer as Dr. Jonas was talking about to identify patients before they get treatment and assign them to the treatment most likely to help them. It's only through that, not just clinical research, but laboratory research that we'll be able to do that in combination. And we really need to increase the funding for those endeavors because they are rather expensive at a time when the NCI's budget is fairly tight. So you hear a lot about personalized medicine in treatment of cancer. We're not yet in the era of personalized medicine for kidney cancer. We are making certain decisions, but they're based on fairly rough guidelines. So for example, we're making decisions based on whether a patient's been treated or has been untreated. We're trying to assign certain risk categories for certain patients based on clinical features that suggest either a good or a poor prognosis. We're making decisions, as we talked about earlier, based on whether a patient has clear cell or non-clear cell tumors, but these are very sort of rough guidelines. We need better ones, obviously, and the hope is that we can come up with markers that are based more on the patient's own genetic profile and the genetic profile of the patient's tumor. So there's a lot of work going on in that as we speak. So recently reported trials, here's a list you've heard some of this before. These were trials reported in the last year. Not all trials are positive. The first one was called the renal effect trial. This was randomizing patients to either the intermittent schedule of sous-tent versus the continuous dosing of sous-tent. The hope was that by giving it a lower dose continuously, it would either be more tolerable or more effective. It turns out there was no difference between those schedules, so they could be used interchangeably. There was another trial with seraphimib where they added on a second angiogenesis inhibitor in hopes of improving tumor control with the second drug added to the standard drug seraphimib. That's the trial in the middle there. And unfortunately, the additional drug, sorry, the additional drug did not improve outcomes to seraphimib. But the last trial on the bottom, which both Dr. Hudson and Dr. Yonash mentioned was a phase three trial, once again a randomized trial comparing now, not a placebo, but a standard of care seraphimib to a new therapy, exitinib, that proved clearly that exitinib was a step forward. It may be a small step forward, but it is a step forward for our patients. And now we have that clear answer. That led the FDA to improving this new, hopefully second generation angiogenesis inhibitor for our patients earlier this year. So what's coming? Well, hopefully drugs that are more effective and less toxic, they're a series of phase two and three trials that are coming close to reporting their results and you'll be hearing about them in the next year. They have names that I listed up here, compares record three T01, which you heard a little about, Torosel 404. We'll talk a little bit about what those are and what to expect from those trials. We also can talk a little, we also talked a little bit this morning about targeted immunotherapy and the role of vaccines and ultimately combinations that might make sense. All of these are being actively tested and we'll know a lot more in the next year. So there are several trials trying to improve upon synitinib, which is the most prescribed treatment for patients with metastatic kidney cancer in 2012. So the compares trial is comparing synitinib with pozopinib, which is votrient. The makers of votrient hope to show that it's as effective as sous-tent and maybe less toxic. We'll see that result later this year. Obviously drugs that are less toxic are worth developing. The other trial looks at the proper sequence of this record three trial. Should you start with sous-tent and then switch to a finitor or should you start with a finitor and then move to sous-tent? So we'll get some more information about the proper sequence of using sous-tent, hopefully with the record three result. We mentioned the Axis trial, which compared exitinib to seraphinib and led to exitinib's approval, which was a step forward. Another step forward, as far as the second generation angiogenesis inhibitors, hopefully will be this TiVo1 trial, which Eric mentioned, which compares a new, more specifically targeted angiogenesis inhibitor to vasinib to seraphinib and showed that it was more effective than seraphinib. So once again, we're coming up with agents that are better than the agents that we had five years from now. Another important trial will compare a standard Tor inhibitor, Toracel, to seraphinib again. And to answer the question, when you failed prior treatment like sous-tent, what's better, to give you another drug like sous-tent or to switch you to a completely different approach, which is the Toracel drug. So we'll be learning a little bit more about the proper sequencing of these agents. And all of this information should be coming soon. The TiVo1sinib data will be presented at ASCO and hopefully the Toracel data will be presented later this year. So combinations, as Eric alluded to, most oncologists think if one drug is good, two's gotta be better. So there've been a lot of combination trials done thus far. Most, I have to say, have been somewhat disappointing. And we'll talk about the reasons why that is, but hopefully as we get less toxic agents and we get smarter about putting these things together, we'll make some progress. You can hear these are some of the drugs that have been used in combination. Certainly laboratory trials have suggested we don't just do this willy-nilly. Certainly laboratory studies have shown that two drugs is often better than one, but there are several important issues. One of them is cost. These drugs, as you all know, are not cheap. The other is toxicity. And so far, many of these combinations have proven pretty toxic when given together. Here are two trials that are combining a blood vessel strategy with Tor inhibitors. This is looking at the record two trial, looks at Bevacizumab and Everolimus together, versus the standard of Bevacizumab and interferon. And the interact trial looks at Bevacizumab and Temserolimus. These are both large trials. It'll give us an answer to the question of is two approaches to attacking the cancer better than just one at a time? We'll see that going forward. As you all know, as we've talked about multiple times today, none of very few of these treatments produce remissions. And we obviously need a second and third line treatments. There are a couple of trials that are accruing that will give us some answers to that. There's another angiogenesis inhibitor, this agent called TKI258, that's now in phase three trials. And it's once again, comparing to seraphonib. So that might be a step forward as well, looking at, in the cooperative group trial, looking at combinations on top of Everolimus, adding Bevacizumab and hoping that that will improve outcomes more than Everolimus does. We'll see. We talked a little bit this morning about targeted immunotherapy and its potential. We talked about vaccine treatments. I alluded to one trial, one phase three trial, looking at combinations with a dendritic cell vaccine and two-tent that's actually more than one trial. This imatics trial here on the right looks at another peptide vaccine, also in combination with Sunitinib. Hopefully that will lead to more durable benefit with this drug. It's great that they're actually being compared in large phase three trials that will give us clear answers, but this information is probably a little bit longer away because these trials are still enrolling patients. We mentioned PD1 antibody earlier. This is one of the more exciting forms of targeted immunotherapy, being developed. Two points that I didn't make this morning that I'd like to make now is this drug should soon be entering phase three trials. It's moving pretty quickly. Hopefully the phase three trials will open later this year and if positive might lead to the drug's approval. But just as importantly, there's more than one PD1 or PDL1 agent in development. These are five separate companies, all of whom have decided this is an important pathway and are developing different ways to blocking this barbed wire that I talked about that protects cells from attack by the immune system. So you'll be hearing a lot more about these agents in not just in kidney cancer, but in other tumor types as the year goes on. This Chris Wood covered this very well early, so I won't beat this to death, but we're also doing clinical trials with drugs that have been shown to improve survival for stage four patients. We're now using them in stage two and three patients and it'll take, as he mentioned, it'll take several years to know if they delay cancer coming back after surgery or they prevent cancer coming back from surgery. Obviously there's a big difference between those two, but we're several years away from knowing these results. But the great news about these trials is they are accruing well. Patients have gone on them very quickly, much more quickly than we expected. So while the drugs themselves may have issues for early stage patients like side effects or when we'll have to see about effectiveness, the patient community has been very motivated to go on trials like this. So hopefully as we get better drugs, we can then test them in the early stages of kidney cancer and prevent recurrences. I mean, that's where we can make a huge impact, preventing the need for treatment for stage four cancer. So in just sort of closing, I think this is obviously one fundamental question for folks who haven't considered doing a clinical trial. Why should I do it? I mean, certainly I think, and I'm obviously incredibly biased because it's what I do, is that I think it gives you access to cutting edge approaches. Now obviously cutting, the newest thing isn't always better and sometimes it's more harmful. We've certainly seen multiple cases of that, but I do think you get access to things sooner than you might if you don't consider trials. And I do think we're doing a little bit better as I mentioned, picking treatments than we were 10 years ago and also picking patients for those treatments. We're a little bit smarter. We're having more positive trials. But all that being said, the participation for cancer clinical trials in the US is still less than 3% of all patients. So when you think about it, I can sit up here and talk all day about all the things I'd like to do and Eric's got great ideas and Tom's got great ideas and Chris Wood's ideas are okay. But we can't do it without participation. And convincing people to come and sacrifice because they are sacrifices to travel and take some risk with newer treatments, that takes a lot. And it really requires mobilization of the whole group of people, the whole community of kidney cancer people. So hopefully events like this will improve people's willingness to participate in trials, getting that message out about why it's important. There are a lot of reasons why you might want to consider it. But one of the questions people ask is what else is in it for me? I know it's in it for the field and other patients, but what might be in it for me personally? One thing you could think about, and this is Dr. Buchowski's slide, but I agree with it. There's some people who think the care on clinical trials is better. You could argue that back and forth, but you're certainly followed much more closely on a clinical trial than you would be if you weren't on a trial. You're being not only watched very closely for side effects with more frequent visits, but you're being watched very carefully for is the treatment working? And there are a lot of rules set up to protect you from not only side effects, but ineffective treatments. There are rules by which we have to remove you from a trial if it's not in your interest. And most importantly, you can always stop at any time you want once you've joined a clinical trial. The other question, which is a little bit harder to address is do patients on clinical trials do better? And he has possibly here on his slide and he notes this interesting data that was just presented last year. This is looking at 238 phase three clinical trials of all cancers done in recent years. And when you look at this slide, it's a little bit complicated. I didn't want to give too much data in this, but I think it's kind of important for the percentage of the 158 trials that reached their goal, as far as they enrolled the amount of patients they thought, which is the sufficient accrual, that was about two thirds of the phase three trials. So not all trials reached their goal for patients, which is a problem. But of those that did, most of those trials showed positive results. In fact, 143 out of 158 had positive results. There were some that had negative results or were closed early because of side effects, but it was a relatively small number, only 15 on this slide. Whereas most, the highest reason for the trial not succeeding, which is a third of trials, didn't get enough patients on them. So this makes a couple points. One, we got to get more patients on trials so we can answer this question. But also a lot of the trials that we're doing have certainly advanced the field, but a help we think the patients who go on them. And you can't, that would be hard to prove, but it's certainly worth considering. There may be some advantages for you as an individual when you're considering clinical trials. So in conclusion, I think clinical trials advance our knowledge and I think they've improved outcomes in kidney cancer. And it's been a great effort by many patients. Over 6,000 have gone on these trials that we've talked about over the day. And not only improving patient outcomes for themselves, but also the future way that we treat patients and coming up with better treatments for people who fail is only gonna happen with research. So we need to keep working on it. We need to define new approaches. We need to extend treatment earlier in disease. And we also need to focus about the patients who are unable or don't qualify for trials. What do we do with those folks? We need to do a lot more research in that area. But hopefully in partnership, we can continue to make progress over the next decade like we made it over this last one. Thank you very much. Join us again next month for another edition of Kidney Cancer News. I'm Kari Konoski wishing you good health.