D. Mitteldorf              Hello, everyone.  Welcome to another of Malecare’s teleconferences on advanced stage prostrate cancer.  Founded in 1997, Malecare is America’s leading men’s cancer survivor support and advocacy national nonprofit organization.  Malecare is the founding member of the Global Prostrate Cancer Alliance and is pleased to announce its newest program to finance cancer research, which we are calling Start a Cure.  You are all encouraged to go to www.startacure.org after the broadcast and learn about the latest research in prostate cancer treatment.

Tonight we are honored to have Dr. James Gulley, a medical oncologist, as our primary speaker.  He is Deputy Chief of Laboratory of Tumor Immunology and Biology at the National Cancer Institute and Director of that group’s clinical trials group.  Since 1999, Dr. Gulley has been involved in designing and running numerous clinical trials in prostate cancer at the National Cancer Institute.  He’s been an investigator on approximately 50 of those trials and has been the primary investigator on 20 of them.  Most of the studies he has run utilize therapeutic vaccines for solid tumors, which will be the gist of tonight’s talk.

Also speaking is Joel Nowak, a social worker and advanced prostrate cancer survivor.  Mr. Nowak is Director of Malecare’s Patient Advocacy Unit, as well as Malecare’s Advanced Disease Program, which continues to be the only national program entirely focused on treatment navigation for the advanced stage prostrate cancer patient.

We wish to thank Bavarian Nordic Corporation for their generous support of this teleconference, to remind you that this teleconference is copyrighted; and we want to thank in particular the individual contributors and volunteers that keep Malecare alive for these 14 years of service to our survivor community.

Listen carefully.  Take notes, and then we’ll expect all of you to live a bit longer as a consequence of listening to this broadcast.

Joel and Dr. Gulley, please take it away.

J. Nowak                     Thank you so much, Darryl.  First, I want to say that what I’m really planning on doing tonight is to review with Dr. Gulley some of the new treatments for metastatic castrate-resistant prostate cancer.  We’re actually going to move into a very, a more significant conversation about therapies known as cancer vaccines or immunological therapies.  We’re going to look at both the approved and the unapproved immune therapies with an expanded conversation about PROSTVAC, which Dr. Gulley has been involved in both the development and the testing.


Welcome, Dr. Gulley, and thank you so much for joining us this evening.


Dr. Gulley                   Thank you, Joel.


J. Nowak                     Good.  Before we move on to our conversation about immunological therapies, I’d like to talk about some of the newly approved therapies and how they fit into a person’s treatment protocol.  The FDA has recently approved a number of these new therapies, Provenge, Firmagon, Zytiga, Xtandi and Xgeva being some of them.  Could you please give us a brief description of these treatments; how they work and when they’re appropriate to use?


Dr. Gulley                   Yes, so it’s a very good question.  Before 2004 there was no therapy that was approved for men with metastatic disease that had failed hormonal therapy that had progressive disease after hormonal therapy.  In 2004 docetaxel was approved based on an improvement in overall survival of about 2.5 months.  Since then, since 2010, really, there have been four new drugs, as you mentioned, approved.


These include chemotherapy agents, such as cabazitaxel, which is used in patients who have previously had docetaxel or other chemotherapy, but perhaps even more recently and more interestingly, the approval of abiraterone or Zytiga and enzalutamide or Xtandi.  Both of these drugs are agents that target the hormonal pathway.  They can really help control disease and bring down the PSA, bring down symptoms, and have been associated with significant improvements in overall survival post chemotherapy on the order of four to five months.


J. Nowak                     I see.  When Zytiga and Xtandi were approved by the FDA, they both were approved in a post or after chemotherapy failure setting.  Since its initial approval, Zytiga has also been approved for pre-chemotherapy.  Xtandi is under trials to try to get the same approval.


A lot of us don’t really understand why once a drug is approved that it’s so specific that why can’t our doctors, along with us, decide what drugs make the most sense.  Perhaps Xtandi is better for me now, even though I haven’t had chemo.


Dr. Gulley                   Yes.  You raise a very good point.  In fact, I believe that eventually we will get the data that will allow us to get reimbursement from the third party payers for drugs like enzalutamide or Xtandi and Zytiga or abiraterone in the pre-chemotherapy setting.  Certainly right now you can get abiraterone approved in the pre-chemotherapy setting, but not enzalutamide or Xtandi.


Now the reason we have to make sure that we have the data is we all think that these drugs are going to work the same before chemotherapy versus after chemotherapy, and perhaps even work better before chemotherapy.  I think that the way that our system is set up, the third party payers require confirmation of the effectiveness of a drug in a particular setting before they’re willing to pay for it.  Perhaps in part this is because these newer drugs are relatively costly with the average wholesale price being in the many thousands of dollars per month.


J. Nowak                     Right.  If and when Xtandi is approved for the pre-chemo setting, how is a doctor going to decide which of the drugs, Zytiga or Xtandi, makes the most sense at which point?


Dr. Gulley                   That’s a very good question.  I typically look at patients that come in with prostate cancer and I look at their other health conditions.  Maybe somebody has diabetes; and so I am perhaps more concerned about starting him on a therapy that would also include steroids because Zytiga, abiraterone, is given with steroids, prednisone, and so if somebody with diabetes goes on prednisone, their blood sugars may be more difficult to control.  In addition, somebody that has thinning bones or osteoporosis, they may also have more complications with steroids than somebody that doesn’t require steroids.  I may be more likely to put this patient on Xtandi.


Those are the types of things that we look at, the side effect profile.  In general, many people believe that Xtandi would be used first, followed by Zytiga.  There’s no data to back that up.  It’s just based largely on the side effect profile and the expectations of potential complications from the steroids.


J. Nowak                     Kind of a similar question, among these other approved drugs, Firmagon and Lupron are somewhat similar in what they do; Xtandi and Casodex somewhat similar, along with Ketoconazole and … and then you have Xgeva and Zometa.  Again, these are drugs that seem to do the same thing.  Are there any trials going on or ways of figuring out which drugs at which point make the most sense?


Dr. Gulley                   That’s a great question, and part of this is going to be from what the patient can bear.  If they are paying everything out of pocket or have considerable copays, it may be certainly a lot cheaper to go with Ketoconazole than Zytiga.  There are some cases where a given clinical situation may dictate what should be done.


If somebody comes in with previously undiagnosed prostate cancer and has significant pain, I would be more likely to give that person something like Firmagon, which should decrease the testosterone levels much quicker than something like Lupron.  There’s not a one size fits all, but I would recommend for the patients out there to go to somebody that is well versed in prostate cancer treatments, because there are lot of these nuances that are important when one is dealing with someone with prostrate cancer.


J. Nowak                     Thank you.  I think that’s an excellent point.  It’s once you’ve had metastatic disease, I know I think that you’re better off at an expert; someone who specializes in the treatment of prostate cancer as opposed to perhaps a general oncologist, who may have a few men with prostate cancer, so I appreciate you saying that.


Dr. Gulley                   Yes.


J. Nowak                     I look at the treatment process that we’ve had for AIDS and, of course, we’ve made remarkable progress there.  My understanding is that a lot of this has come because we now have these cocktail treatments or mixture of drugs.  Are we going to see that in prostate cancer and how is that going to come about?


Dr. Gulley                   Great question.  Thus far most of the therapies in prostate cancer have been single agents given sequentially.  I think that there certainly is a role for combination studies.  There are a large number of combination studies ongoing now.  There have been in the past multiple experimental agents combined with chemotherapy.  None of those have really shown any benefit for the addition of the experimental agent to the chemotherapy in large randomized studies.  There are several that are still ongoing, however, and maybe one of those will show benefit.


However, I would say that some of these newer agents, and it’s just been since 2010 that really we’ve had a significant broadening of our arsenal against prostate cancer, I think some of these newer agents have the potential to combine with other agents, certainly immunotherapy combined with hormonal therapy or two different hormonal therapy compounds combined together, or even Alpharadin, which is not yet approved, but hopefully will be soon approved, could be combined with any of these two.


J. Nowak                     Right.  Now you’ve mentioned large, randomized trials.  For those people who aren’t familiar with clinical trials, can you talk about what that means and why it’s important?


Dr. Gulley                   Sure.  First let’s talk about some of the naming that we’ll mention when we talk about clinical trials.  You’ll hear things like a Phase I clinical trial or Phase II or Phase III.  The Phase I study is the first in human study of a compound or a combination where we’re really looking to get an idea of is this safe to give.  A Phase II study tries to determine is there any evidence that this drug might work and get some kind of an idea of how well it works.  The Phase III study is a study where there is a comparison of a drug or a combination of drugs compared with a standard of care regimen.  Sometimes that could be a placebo because there may not be a defined standard of care, or sometimes that may be another active therapy.


These large studies are really needed because we need to be able to improve upon our current treatment regimens, and if we can show that something new is better than what we currently have available, then I think we can make progress and work in lengthening lives of men with prostrate cancer and other cancers, and learn more about how these agents work, what potentially one can combine with.  This could be potentially useful for a wide variety of other cancers.


J. Nowak                     Right.  If I were interested in participating in a trial, how would I go about learning about them or finding them?


Dr. Gulley                   It’s a great question.  I think the best way to look for a clinical trial is to get on the Internet and go to Cancer.gov.  If you go to www.cancer.gov or under there you can search for clinical trials that are specific for cancer.  The other site that is a government site is Clinicaltrials.gov.  That has clinical trials for everything, including cancer.  Either of those sites will give you a wide variety of different studies, whether it’s studies anywhere basically in the U.S.  Whether they are sponsored by the National Cancer Institute or by a pharmaceutical company, all of those studies will be listed there.


J. Nowak                     Right.  What is the value of a man participating in a study?


Dr. Gulley                   The only way we can make progress, the only way we can get a drug first to see if it’s safe to give and then to see if it’s effective is by doing these clinical trials.  That’s the only way that the FDA will approve a drug for use in patients, so your doctor can prescribe them.


Unfortunately, among patients with cancer, less than 5% of patients ever go onto to a clinical trial.  This is something that I think is standing in the way of us being able to do research and get new drugs to patients quicker.  If more people would make sure of these clinical trials, I think it would be the new drugs would be more plentiful and they would actually be cheaper because the trials wouldn’t take as long to complete.


J. Nowak                     Is there any point in someone’s prostate cancer disease process that they should actually consider a clinical trial?


Dr. Gulley                   You know, that is a fantastic question, Joel.  There are clinical trials from prevention of prostate cancer to brand new diagnosis of prostrate cancer where most people think I’ll just have surgery or radiation or whatever the doctor suggests.  There are trials in that group of patients in that disease state that would potentially help keep the cancer from coming back in patients that are at high risk.  There are studies that may not benefit the patients getting the experimental therapy because maybe they would have been cured anyway, but they may help us understand this drug process and they may help us understand and be better able to treat patients who are at even higher risk.


J. Nowak                     Basically any stage of your cancer is a stage to consider?


Dr. Gulley                   Any stage is a stage to consider.  There have been more studies in the more advanced setting, but don’t think that just because you don’t have advanced disease that there’s not a trial for you.


J. Nowak                     Terrific.  Now I know that your true love is immunology.


Dr. Gulley                   Yes.


J. Nowak                     I’d like to move a little bit in that direction.  First what is the immune system and how does it work?


Dr. Gulley                   Great question.  The immune system, most of us when we think immune system, we think white blood cells.  We know that much, but really your immune system is the entire system that is geared towards keeping your body free from disease; whether it’s a virus, a bacteria, or even cancer.


The skin, for instance, is actually an important part of your immune system.  It helps keep bacteria out, etc.  If that get compromised, such as significant third degree burns, you have a much higher likelihood of having infections and complications resulting from that.  But—


J. Nowak                     And—


Dr. Gulley                   No, go ahead.


J. Nowak                     Go ahead, no, please, go ahead.


Dr. Gulley                   I think most of us, though, think of the active part of the immune system, so the skin is passive.  It replaces itself, but it really doesn’t do much, other than it forms a physical barrier.  The active part of the immune system is really the cellular immune system that is largely within our blood.  It’s really divided into two components.  One component is a component that can recognize and attack different microorganisms or cancer in a non-specific manner.  The other component is a component that can recognize in a specific manner so that each cell is targeted for a specialized target, so you might have one cell that is just specific for PSA and can recognize cells making PSA and can attack those cells.


J. Nowak                     Does the immune system attack cancer?


Dr. Gulley                   Yes.  In fact, there is probably cancer arising in each of us on a frequent basis.  We don’t know how frequent because the immune system does a really good job most of the time in looking for the cancer and killing it before it causes any clinical symptoms.  It may only be one or two cells that start to grow that are wiped out, but something along the way goes wrong in some people and eventually those cells grow, and for some reason the immune system ignores them; and that’s where we run into trouble.


J. Nowak                     I know that for many years people working looking for cancer vaccines—and actually before I even go there, I got a vaccine for polio, but I never had polio, but I know that cancer vaccines are a little different.  Would you kind of explain that because sometimes that’s confusing?


Dr. Gulley                   Yes, it can be very confusing.  When we talk about vaccines, most of us think of vaccines for infectious diseases like polio, like you mentioned, or flu.  Those are also called preventive vaccines, so they can prevent disease.


When we’re talking about cancer vaccines, we’re talking usually about therapeutic vaccines, so these are vaccines that you give to someone, once they’ve already have a disease, something that you can basically use to train the body’s immune system or retrain the body’s immune system to be able to recognize and attack the cancer.


J. Nowak                     Right.  I know researchers working in this field that have been outliers and I think a lot of your fellow researchers have always kind of scratched their head as to what you’re doing with the immune system; you’re wasting your time.  But this has dramatically changed in the last few years.


Dr. Gulley                   Yes, it really, really has.  There have been really since the approval of Provenge, or sipuleucel-T, that is the very first therapeutic vaccine that was approved for any cancer.  Since then there’s also been some dramatic breakthroughs with an antibody that can help program the immune system and strengthen the immune system for patients with melanoma, and that has improved survival for patients with melanoma.  This has really created a quite a buzz in the oncology community, and now there are multiple programs looking at the immune system and ways to stimulate further the immune system.


J. Nowak                     Right, so people who are doing this research used to be outside of the circle and now you are the fair haired—


Dr. Gulley                   Yes, now we’re mid center of the circle and everybody is banging to get in.


J. Nowak                     Yes.  Now you mentioned Provenge.  Could you tell us a little bit about it; what it does and how one gets it and when one should get it?


Dr. Gulley                   Sure.  Provenge is a vaccine that is made by taking blood from a patient in a process called apheresis.  Basically what that is, is they put a tube in the arm just like if you’re giving blood.  The blood comes out and goes into a machine that takes out the white blood cells, some of the peripheral, what we call peripheral blood mononuclear cells, but essentially just the immune cells, and then gives back all of the red blood cells and the platelets and the plasma and just hangs on to some of these white blood cells.


This product then is sent to a central facility where they make the vaccine.  How they make the vaccine is they take these cells and they add something that is a target; and this target is prostatic acid phosphatase and it’s linked to a immune stimulatory molecule called GMCSF that helps stimulate the white blood cells.  This fusion protein is put in the white blood cells and that really helps to get the white blood cells to recognize, and in theory when they’re given back to the patients they should be able to train the other immune cells there to be able to recognize and attack the cells making this prostate antigen called prostatic acid phosphatase.


J. Nowak                     Right.  Who should consider getting Provenge today?


Dr. Gulley                   The labeled indication for Provenge, that what the FDA has approve in the Center for Medicaid and Medicare Services pays for, is patients who have rising PSA on hormonal therapy, so on Lupron.  If their PSA is going up and they have metastatic disease on scan and not significant symptoms from their disease, then those patients would be good candidates, potentially, for this therapy.

Now the studies suggested that there was on average a little over four month improvement in overall survival, but it looks like in a paper that just came out this month that the earlier you start this, the better off you are.  There’s data suggesting that if in the group of patients with the lowest PSA on the Phase III study, those patients did substantially better getting the Provenge than the placebo in that group.  That difference was about 13 months in the lowest group of patients, so it could be that a subset of patients, a part of the patients who have lower disease, may actually have more benefit than patients with more advanced disease.  It’s harder for immune system to work with the more advanced disease.


J. Nowak                     Right.  I’m drawing from this that once one becomes castrate-resistant or their hormone therapy stops working and they have metastatic disease, they should probably give serious consideration to Provenge sooner than later.


Dr. Gulley                   Yes.  When we have talked about this in think tank sessions, we thought how are we going to sequence this all if somebody has no symptoms and their PSA is just kind of slowly going up, would we give them Provenge first?  The answer is a lot of us have said yes, maybe Provenge first and then after that then follow that with Xtandi and then ride that for as long as we can and then maybe Zytiga, and on down the line.


J. Nowak                     Right.  You’ve been very involved in the development of another immunological treatment called PROSTVAC.


Dr. Gulley                   Yes.


J. Nowak                     Can you tell us about that?


Dr. Gulley                   Yes.  This is a very interesting therapeutic vaccine that was developed here at the National Cancer Institute.  I’ve been here about 15 years and we’ve been working on that most of this time.  It is a vaccine that basically instead of requiring blood to come out of patients, it is a vaccine that you can just take out of the freezer and inject into patients.  It’s what we call an off-the-shelf vaccine.


Now what is this vaccine?  It actually is a virus that has been modified to express PSA, as well as three different genes that really help boost the immune system significantly.  These are called T cell costimulatory molecules, and these really give a significant boost to the immune system, specifically to the T cells.  The T cells are the part of the immune system that do the heavy lifting when it comes to fighting cancer.  In fact, in mice, if you wipe out their T cells, the vaccine doesn’t work at all, but if you take other parts of their immune system apart, it will still work for the most part.


J. Nowak                     Now I know there’s currently a Phase III trial, which is the one looking, as you’ve described before, as the large randomized trial making sure it’s safe and that it works.  Can you share with us to results of the Phase I and the Phase II trials?  I think they’re pretty exciting, actually.


Dr. Gulley                   Yes.  I do, too, actually.  Thank you for asking.  The initial studies, the Phase I studies showed that it was very safe.  There were no serious adverse events or side effects from the vaccine.  The Phase II studies, there were several.  I’m going to mention two of them when we’re talking about just the vaccine by itself.


The first one I’m going to mention is a study that was done here at the National Cancer Institute.  It was a relatively small study, 32 patients, and what we saw was that we could generate very, very nice immune responses in patients.  Those immune responses were specific for the vaccine.  We were targeting PSA.  We could see before giving the vaccine compared with after giving the vaccine, the number of T cells that targeted PSA went up considerably.  When we looked at the overall survival of the patients, there was a hint—it’s a very small study, so I don’t want to read too much into it, but there was a hint that patients who had the best immune responses also did better in terms of survival.


What was even more interesting, though, in the Phase II studies, is a second Phase II study that was done at some 43 different centers across the United States.  In this study 125 patients were enrolled and treated with either vaccine or placebo.  What we found from this study was that there was an improvement in overall survival in those patients treated with vaccine of about eight and a half months.


Now this is pretty good for patients for clinical trials of products in metastatic prostate cancer.  All of the approved products have an improvement in survival of between 2 and 4.8 months, so this is quite encouraging for us.  However, it is a relatively small study, only 125 patients, and so that is why we’re doing the larger study to follow up on these results.


J. Nowak                     I see.  Where are we with that Phase III study?


Dr. Gulley                   Very good question.  We have the trial open in; I believe it’s about ten different countries right now something like that.  It’s open in the U.S., Canada, Puerto Rico, as well as many countries in Europe and Israel.  It will soon open in several other countries in Europe and in Australia.  We have close to 100 sites that are enrolling patients and I hope that by this time next year we will have completed enrollment.  Our estimated enrollment completion will be at 1,200 patients.


J. Nowak                     Right.  Hopefully, you’ll complete enrollment within a year.  That’s the goal.


Dr. Gulley                   Yes.


J. Nowak                     From that point how long would it take to actually see statistical results that will tell us whether this works or not?


Dr. Gulley                   That’s a great question.  There is a plan to look at the data not after—if we had to wait till every patient, if we knew if every patient was going to live or not live on the study, we would have to wait a lot longer.  Typically what we do is we say we’re going to pick a time when we have a certain percentage of the patients that have died and then we’re going to look at the data.  We’re going to consider that final, because there’s often patients that do significantly better than the average and it would be a long time to wait to get all of the events.


However, in this study we are going to be not just looking at the 80% or whatever the cutoff would be.  We’re actually going to be looking early, too, and if we see a signal earlier, we could close the study earlier and present to the FDA.  It’s not really clear how much longer after next year we would need to wait, but it’ll be at least a year after that.


J. Nowak                     Right.  Now I if have my information correct, there was a stage II trial that basically showed that there was no evidence of improved progression free survival, but it did have a statistically significant improvement in overall survival.  Is that correct?


Dr. Gulley                   That is correct.


J. Nowak