Advaxis, Inc. (NASDAQ:ADXS)
Investor & Analyst Day 2016
June 28, 2016 01:30 PM ET
Daniel O'Connor - CEO
Greg Mayes - COO
Bradley Monk - Lead Cervical Cancer Advisor
Warner Huh - Senior Scientist at the University of Alabama, Birmingham
Brian Slomovitz - University of Miami Miller School of Medicine
Lisa Kachnic - Associate Director Multidisciplinary Cancer Research, Boston University
Mark Stein - Oncologist, Cancer Center of New Jersey
Good afternoon. My name is Greg Mayes, I'm the Chief Operating Officer at Advaxis and on behalf of the management team, I would like to welcome you to our Second Annual Investor and Analyst Day here at the offices of Reed Smith in New York City. Thank you very much for coming. Our first speaker is our President and Chief Executive Officer, Daniel O'Connor. I'd like to welcome him to the stage.
Thank you, Greg. Okay, good afternoon and thank you to everyone for joining us here on our Second Investor and Analyst Day in New York City and welcome to those who are joining us by webcast. Special thanks to Reed Smith for opening up their offices for us, we definitely appreciate that, thanks a lot. And there's some seats upfront, if anybody would like to seat down upfront.
Okay, before we begin I'd like to note that we may be making some forward looking statements during this presentation. Please take a moment to read our public filing filings filed with the SEC, please also take a moment to read the slide, okay thanks.
So this afternoon we’re fortunate to have several outstanding oncologists who have participated in clinical trials with Advaxis’s product candidates here to discuss their work. We have a great line up and we appreciate each of them travelling from their respective hospitals and centers of excellence to be here with us today. Before they begin, I’d like to take a moment to highlight some of the developments that have occurred at Advaxis over the last several months.
Let’s start with Axalimogene filolisbac, a.k.a AXAL for short. AXAL is a targeted immuno therapy for the treatment of patients with HPV-associated cancers. AXAL and our other product candidates using Lm technology conceptually started out as a vision to exploit the relationship between an intercellular pathogen Listeria monocytogens or Lm and it’s perceived host antigen presenting cells, such as dendritic cells. They educate the immune system to recognize and affectively attack cancer cells.
The first half of 2016 has been both very important and informative for AXAL in that this vision has now manifested evidence that Lm technology has the effects in the microenvironment -- the tumor microenvironment of the macroscopic environment to the macro environment of patients and developing technology resulting in meaningful clinical activity. So I’d like to make five overall points with regards to AXAL. First, when I joined Advaxis, the company had data from the study conducted in India showing that AXAL appears to have mono-therapy activity in patients with pre-treated recurrent cervical cancer.
This study gained the attention of the GOG, the gynecologic oncology growth and they decided to design and conduct a study exclusively in the United States using AXAL to treat women with persistent or recurrent cervical cancer who had failed all prior therapies. This federally funded study is known as GOG-0265. Data from the 265 study for which Dr. Warner Huh is the principal investigator seated at the table there, were selected as an oral points [ph] to discussions at ASCO in June.
I’d like to make two observations about the 265 study from my point of view thus far. Observation number 1, there were numerous immunotherapy product candidates presenting data at ASCO this past June. AXAL was among the very few immunotherapies that reported a durable complete response as a mono-therapy in patients with recurrent relapse metastatic cervical cancer and it was among the few that reported durable complete response in any solid tumor types. Two others were nivolumab which is Opdivo and pembrolizumab which is known as keytruda. Now there is saying that you’re pictured by the company you keep, we like that company.
Second observation, pembro or keytruda presented data at ASCO with 24 patients in relapse refractory metastatic cervical cancer. When you look at the pembro activity and the pembro data, relative to Advaxis AXAL 265 data, I think the AXAL data looks good, especially when you consider that the pembro study selected for patient with high PD-L1 expression levels.
Okay, so here is my second point regarding AXAL, three years ago Advaxis was among the very first immunotherapy companies to seek to combine Lm product candidates with other immunotherapy agents to see if any potential synergy activity could be observed. Now forward to today, Brian Slomovitz the principal investigator, again seated at the table, is the PI on the study combining AXAL and AstraZeneca, MedImmune and durvalumab in late stage cervical cancer. Brian will be presenting a case study showing that combining AXAL with durvalamab is not only feasible but resulted in a complete response with one of the early patients as well as acceptable safety, though again Brian will discuss these data shortly. For those of you keeping score, this is the second CR in late stage cervical cancer reported in the month of June.
Okay, third point. It’s especially important -- especially it’s very important, especially for small companies to ensure its footing to be as confidence as possible on the path you’re taking which could ultimately lead to the approval of a product candidate. One tool to ensure that footing is solid is by developing a protocol under the FDA’s Special Protocol Assessment program or SPA program.
This is a great tool because it allows company like Advaxis to gain the FDA’s review and comment regarding the protocol beforehand, it front loads this review and fosters a dialog between the regulatory authorities and the company to ensure that the protocol is adequate. As many of you know, Advaxis has been in this thought process with our aims and service protocols for the past several months. Aimed to service as our planned Phase 3 registrational trial for AXAL in its treatment of high-risk locally advance cervical cancer.
A successfully conducted stop provides an agreement that the Phase 3 trial design conduct and planned analysis adequately addresses the scientific and regulatory objectives in support of the regulatory submissions for drug approval. On course, final marketing approval depends upon the efficacy results, the safety profile and the evaluation of the risk benefit treatment demonstrated in the Phase 3 clinical study. This thought process is rigorous and time consuming, no doubt but our productivity I believe in seeking the spot will give us stronger footing on the regulatory pathway and will be well worth the time and effort we spent to frontload the review of the AIM2CERV protocol and I believe that we’re close to finishing the process.
Okay, fourth point. Before she passed away from anal cancer Farrah Fawcett formed a foundation to find a cure for the disease. Her organization known as the Farrah Fawcett Foundation sponsored the study of AXAL and the treatment of high risk locally advanced anal cancer at the Brown University Oncology Group. You will recall that earlier February 12 at this setting [ph] last year, we announced encouraging preliminary data showing that there was no recurrence within the protocol prescribed time frame in all 10 patients who completed the treatment regimen of AXAL with concurrent standard chemo radiation treatment and these patients were all considered to be high risked recurrence.
Because of these data and other AXAL data the Radiation Therapy Oncology Group or the RTOG is interested to open up their network of oncologists and radiologists to conduct a randomized Phase 3 study in high risk locally advanced anal cancer. Dr. Lisa Kachnic is here to provide us with full perspective about this opportunity shortly. We are grateful that the RTOG is interested to commit their network and manpower to conducting a study which would constitute that second registrational quality study for AXAL in a different tumor type where the unmet medical need is extremely high.
Fifth point regarding AXAL, I’d like to briefly discuss some of my thoughts regarding the AXAL data from an ongoing Phase 2 study with AXAL in patients with late stage HPV-associated head and neck cancer. These data were selected for late breaking poster discussion session and then presented at AACR last April. For the past several years, the folks at Advaxis have known that our preclinical experiments, that Lm technology has the capability of affecting the TME of the tumor microenvironment to make tumors more susceptible and immunological attacks pre-clinically. This data has been published in several peer review journals.
However as we know many theoretical effects get lost in the translation from pre-clinical work with mice into human clinical trials. We’re afforded a narrow window of time to study these potential tumor microenvironment effects through a collaboration with Mt. Sinai Hospital and Baylor College in patients with head and neck cancer that have the five week window of time between their initial biopsy and surgery to resect their tumors. This five week window allowed for an abbreviated regimen of two doses of AXAL.
Immunotherapies are generally understood to work better over time though we were unsure whether we could expect to see any changes in the post treatment setting. We were pleased that the post treatment tumor tissue analysis performed during the trial showed that in several patients there was conversion of the tumor microenvironment into a site of active inflammation characterized by the infiltration of activated T-cells and increased expression of activation markers for an immune response. In other words with only two doses of AXAL in a short five week window, it's beginning to look like AXAL can switch the immune system in the microenvironment off and recruit the key players necessary to mobilize an immune response to the tumor.
Now, let’s look beyond AXAL. We have three other product candidates using our core Lm technology that are currently getting their feet on the ground, two are already in clinical trials and a third is moving in that direction later this year. The two product candidates currently in clinical trials are Advaxis HER2 and Advaxis PSA. We’re developing Advaxis HER2 to target cancers expressing the HER2 receptor and are currently running first in human Phase 1b dose escalation study for the treatment of patients with metastatic HER2 expressing solid tumors including breast, gastric, oesophageal and osteosarcoma.
We were awarded fast track designation by the FDA in April for patients with newly diagnosed non-metastatic surgically respectable osteosarcoma. Our second product candidate, our third actually that’s in clinical development, Advaxis PSA. This program is focused in targeting the prostate specific antigen or PSA that is expressed on prostate cancer cells. We’ve a Phase 1/2 study ongoing investigating our product candidates access to PSA in combination with Merck’s KEYTRUDA or pembro for the treatment of advanced metastatic castration resistant prostate cancer.
Our goal is to have this study fully enrolled by the end of this year. Pre-clinically let’s look at Advaxis Neo. Advaxis Neo is our preclinical product candidate which in place of targeting the well-known and well established cancer targets instead targets agent specific unique mutations known as Neo-Epitopes, which are obtained for the biopsy of an individual patient’s tumor. We believe that these patient specific unique mutations may comprise important targets against which anti-tumor CDA positive T-Cells can be generated leveraging our Lm technology. We call this program MINE which stands for My Immunotherapy Neo-Epitopes. We’re working with important groups such as Memorial Sloan Kettering to develop Advaxis Neo.
Our Web site has a video which explains Advaxis’ Neo, I’d encourage you to watch it because it's excellent. You will be hearing more from us about MINE and Advaxis Neo as we move forward with this pre-clinical product candidate and prepare to file an IND later this year.
Okay. Milestones. As we look to the second half of 2016 we anticipate achieving a number of important value enhancing milestones. One such milestone is the planned initiation of enrollment in the AIM2CERV study. We also plan to submit preliminary AXAL Durvalumab combination data from the ongoing study that Brian will speak to in a moment, to SITC or the Society of Immunotherapy of Cancer for presentations if selected at their annual meeting in November.
Alright, let's take a look at manufacturing. I would like to make a comment about manufacturing. From my point of view next to safety and efficacy, manufacturing is probably the most important other element for cancer immunotherapies and for product candidates moving from the clinic and into the commercial setting. We have designed and implemented a simple robust process to manufacture our own product candidates. We also continue to evolve the process with the ultimate goal of delivering commercial process that’s reliable, compliant and highly cost effective.
Over the past year we evaluated numerous options for our supply chain. In particular we analyzed whether to make or to buy and concluding that building our own internal manufacturing capability made the most sense. Construction of a new flex suite for both as GMP clinical production and process improvement at our Princeton facility which also has our laboratories, has now been completed. An additional expansion facilities is also underway to provide both clinical production capacity and future commercial capacity. These are important steps for the company and these new capabilities will provide us with both a very competitive cost structure and the flexibility to respond quickly to the needs of our clinical programs.
I would now like to take a few minutes to step through how our proprietary Lm Technology works. Since this is the common denominator to all of our product candidates and in fact is at the heart of our company. So, by now we know that the human immune system is capable of recognizing and killing some cancers. So why doesn't it do it all the time, is really the fundamental question. How have cancer cells been hiding from the immune system?
One way is that unlike a virus or a bacteria which truly expresses foreign materials cancers often contain multiple maturations in different genes spread out around a large background of normal human proteins. Some tumors are even made of populations of cells that have mutated differently, so the target is fundamentally unclear. These tumors also recruit guards in the form of myeloid-derived suppressor cells commonly known as MDSCs and regulatory T-cells known as Tregs, they help keep whatever immune systems cells that might approach to destroy them away from doing so.
In addition, those guards, the myeloid-derived suppressor cells and MDSCs and regulatory T-cells or Tregs tumor cells often express in themselves and induce expression in surrounding tissue immunosuppressive signals like PD-1 which adds to the kind of fundamental protective custody in the immunosuppressive tumor micro environment, really stopping the immune system from attacking and getting out the cancer.
So the mechanism of the immune system uses to kill cell that are infected with viruses and intercellular bacteria are the same key players in activation pathways that are necessary for anti-tumor immunity. So, our technology uses an intercellular bacteria Listeria monocytogenes, which naturally triggers many post defense mechanisms by engineering the bacteria to express tumor-associated antigens such as the prostate specific antigen, the human papilloma virus, HER2 and now Neo antigens we can educate the immune system to direct and attack against the cancer.
So, this slide is a slide that we frequently refer to, to describe the technology and the heading of the slide is important, it reads harnessing unique lifecycle of Lm in APCs, antigen presenting cells think of that as dendritic cells macrophages So, we start with Listeria monocytogenes, the technology was invented at the University of Pennsylvania. We are fortunate to have the inventor here today, Van Patterson [ph] and refined and further invented at Advaxis in Princeton.
So, we start with a bacteria, gram positive Listeria monocytogenes. We engineered the bacteria in two ways, first we attenuate it. Basically we prevent it to being able to spread from cell-to-cell like the wild type pathogen normally would. Second element of bioengineering is we transfect or we insert DNA plasmids, the way to think about these plasmids are like many protein factory and I will describe the role that they play in a moment. So with those two forms of genetic engineering we dose patients with a billion bacteria over approximately one hour in an infusing clinic.
Those bacteria enter the blood stream and are taken up preferentially by antigen presenting cells which do what their name says they do, they present antigens typically dendritic cells. The antigen presenting cell or dendritic cells engulfs the bacteria and brings it in as something known as the phagolysosome, a way to think about that is basically an acidic vacuole. Now the wild type Listeria monocytogenes and our attenuated strain of the bacteria fundamentally do the same thing in this setting, they secrete a LARS [ph] in protein which enables the bacteria to escape destruction in this acidic vacuole, the phagolysosome and the bacteria then exits into the cytosol of the antigen presenting cell.
That was the ‘Aha moment’ moment for the technology and that's why the inventors at Pen [ph] and Advaxis said, hey that gives us an opportunity that exiting the phagolysosome and getting into the cytosol of the antigen presenting cell gives us a unique opportunity to present antigen in the cytosol as a perceived intracellular infection, for which you need cytotoxic T-cells to eliminate such an infection. So how does that work? Again the bacteria gets involved, it secretes LLO, LLO is alive in protein, it then basically breaks open the phagolysosome and the bacteria has now escaped into the cytosol or the open space of the antigen presenting cell.
There that genetic engineering, bio-engineering I mentioned a second ago, the DNA plasmids do their job. So we take DNA plasmids, we insert it or transplant it into the bacteria, those plasmids turn on when the bacteria is in cytosol and now they’re secreting what we call a fusion protein. What is the fusion protein? Basically two elements, one truncated LLO, which is highly immunogenic it’s the same protein that was used to cause the bacteria to escape out of the phagolysosome, our body do not like LARS in proteins. So that protein stimulates a very strength immune response.
That LARS in protein truncated LLO fuse to attack a cancer target. This is really fundamentally the reason why I joined Advaxis, because of that unique capability. We can select essentially any target, we want to select for presentation in that matter. To date human papillomavirus, vital antigen, PSA, HER2 and now neoepitopes. So that bacteria is now inside of the cytosol secreting a attenuate so it doesn’t spread to the adjacent cell, but presenting protein in a very unique fashion against circling through the body, you need to create a cytotoxic T-cell or CD8 positive T-cell to eject the bacteria pathogen.
When that happens these proteins travel alone, the secreted protein travels alone MHC class I pathway, which eventually results in CD8 positive cytotoxic T-cell to the target being formed. That’s only half of the equation with the Advaxis Lm Technology. The other half is contextual, this happens in the context of the perceived overwhelming bacterial infection, which as I said earlier stimulates multiple aspects of the Immune Response.
So I hope that was just a good foundational learning for our technology and again as I said it’s the common denominator through all the product candidates to which we will be talking about today. So now it’s my privileged and pleasure to introduce the speakers that have agreed to come and present to you today. The first is Dr. Bradley Monk. Dr. Monk recently agreed to serve as Advaxis’s Lead Cervical Cancer Advisor which Dr. Monk, we greatly appreciate. Dr. Monk is the Director of the Gynecologic Oncology at St. Joseph’s Hospital and Medical Center in Phoenix, Arizona. He is also the Chair of the NRG Oncology GOG Cervical Cancer Sub-Committee. Dr. Monk is going to discuss our planned AIM2CERV Phase 3 study with AXAL in cervical cancer.
Following Dr. Monk will be Dr. Warner Huh. Dr. Huh is a Professor and Division Director of Gynecologic Oncology and Senior Scientist at the University of Alabama, Birmingham. He is the Principal Investigator of our ongoing Phase 2 GOG-265 study in cervical cancer and he is going to review the data from that trial including the results that we just recently presented at ASCO.
Following Dr. Huh will be Dr. Brian Slomovitz. Dr. Slomovitz is the Director of the Gynecologic Oncology Division and the Department of Obstetrics and Gynecology at the University of Miami Miller School of Medicine and also leader of the Gynecologic Cancers Site Disease Group at the Sylvester Comprehensive Cancer Center in Miami. As I mentioned earlier, Dr. Slomovitz is the principal investigator of our study combining Advaxis AXAL and Durvalumab and Dr. Slomovitz is going to walk us through his observations with respect to that study today, in particular one patient case study.
Following Dr. Slomovitz will be Lisa Kachnic. Dr. Kachnic is an Associate Director of Multidisciplinary Cancer Research at Boston University. And Professor and Chair of the Radiation Oncology at Vanderbilt University and will discuss the AXAL anal cancer program.
Following Dr. Kachnic, you will hear from Dr. Mark Stein, who is a medical Oncologist at the Cancer Center of New Jersey. Dr. Stein is the investigator on our ongoing Phase 1, Phase 2 study evaluating Advaxis-PSA with metastatic castration-resistant prostate cancer in combination with [indiscernible] and that will be the focus of his discussion.
One of the core value at Advaxis is being grateful, being grateful for what we’ve being given in this technology to shepherd it through the drug approval process and the clinical trial process. Being grateful for the investigators who have agreed to stand by our side and work with our technology. Being grateful for our shareholders, who have from the beginning been with the company to help us shepherd this technology through and to support us.
And our employees, I would be remised to not mention them as well. But most importantly we’re grateful to the patients in our studies. The patients in India who participated in our studies years ago, the patients who have participate in the 265 part 1, the patients that are enrolling in studies today and getting treated today with our technology and the patients that we’ve planned to treat in the future.
So with that, I’ll say thank you very much and turn it over to our first speaker. Dr. Brad Monk.
Thank you and good afternoon Dan. You’re a wonderful speaker, thank you. I can feel your enthusiasm and it’s well founded and certainly legitimate. It's my honor to be with you today, I would like to spend just a few minutes and talk to you about a virus, bees [ph] and ultimately a study, Dan has already introduced to you his AIM2CERV.
Mostly going to talk about the Human Papillomavirus, you guys know it as HPVs, it’s the most common sexually transmitted disease. We first recognized in the early 1800s that prostitutes had at high incidence cervical cancer. It created the wrong message, don't need to be sexually deviant or promiscuous to get cervical cancer, and doesn’t need to have sex, but even my mother and she's the best women in the world.
So, [indiscernible] changes under the microscope, they were present in the healer cells, Harald zur Hausen discovered this double stranded DNA virus and ultimately got the noble price for its biology. 79 million people, any of you in this room, 80% of sexually active women will be infected by this virus. Fortunately, you never know you had it generally, fortunately you can get over it, but many of us do not resolve the infection because of the immune environment, we're going to talk about that and ultimately if the virus is not subjected and treated you can get the answer and that's what we're here to talk about.
So, the virus causes cancer, I think you guys get it. Certainly not everyone that has the virus gets cancer, but it still is -- it's very common. So, this slide shows the number of new cases attributable to HPV and the percentage. So 528,000 cervical cancers that are all caused by HPV. 88% or 35,000 anus cancers, 41% or 20,000 vaginal, vulvar, penile cancers, head and neck cancers which you're going to hear about. 56,000 HPV attributable cancers in men, 575,000 cancers in women. Now what happens is people say yes, that’s mostly driven by cervical cancer, that's mostly driven in under developed countries and that's probably true, East Africa, West Africa you can see the incidence in the mortality rates, incidentally this is the disease I told you I'd talk to you about the virus first, the disease second.
This is a vaginal excision, this is the cervix and this is normal cervical tissues, there is legion here in the cervical cancer, this is a radical hysterectomy specimen, uterus is here out and the ovaries are there. So although it is a disease of the developing world, it's also a disease of the United States of America, okay. It's important, that's why we're here.
Almost 13,000 new cases, almost a third of them die, 4,120 deaths. So this disease is here and we need effective ways to deal with it and I'm very honored to be here and work with Advaxis who's the leader in developing effective therapies for HPV related cancer. We know where these women are, they are in various parts of the country and we're here with an expert Dr. Slomovitz from Florida, we're here with an expert from Alabama and certainly I'm here from Arizona, but we know where these women occur. And I also have to say look I get it that HPV vaccination will save their children, you should get your boys, your daughters vaccinated and they get vaccinated when they’re 10 to 12 years of age and we will prevent them from getting cancer when they're 40 to 50, it can be 30 years from now.
So, don't tell me that HPV is related to promiscuity, don't tell me that it's only in the third world and don't tell me that vaccination has already solved the problem. So, what happens is that we treat patients and we need to stimulate their immune system as part of the maintenance strategy and that's the third point, the [indiscernible] study, we did get bevacizumab approved in 2014 but this is for recurrence. Our mission is to cure more women, to prevent recurring. This is a small step forward in treating recurrence, but we need to prevent it right. So, we can pretty much tell who's going to recur and those are the patients that are our best opportunities for clinical benefit with AXAL.
Certainly at stage, we've a staging system called FIGO, Fédération Internationale de Gynécologie et d'Obstétrique staging, and you can see how large these tumors can be, either stage three tumors, it's a very large tumors where the risk of recur is high. And these tumors which are too large for a surgery, remember I showed you a radical hysterectomy, the cases that are too large for a surgery are treated with chemotherapy, external beam and an implants put right in the cervix and weekly chemotherapy, the global standard MCCM recommended level one evidence and these -- it's a lot of radiation, it radiates the pelvic area, this is the front to back, this is the side, this is the uterus, the bladder, the rectum and we radiate the cervix, external beam and brachytherapy and it's really effective.
You can see here a very large cervical cancer, this is three dimensional, very large, this is the cancer, this is the uterus and you can see that after radiation therapy it goes away. But you can recently predict which one of these cases will come back, I already told you stage, advanced stage three and four and when it’s in the lymph node, this is a PET scan, these are lymph nodes that are taking up the radioactive sugar in a PET scan and are positive, in fact she even has one in her neck.
This patient is in trouble and although she may respond to chemotherapy and radiation, her chance of recurrence is very-very high. Very-very high, and again stage is another way to figure who is going to recur and again these are ideal opportunities for immuno-maintenance therapy after chemotherapy and radiation. So HPV associated cancers evade the immune system, that's the problem. They down regulate MHC Class 1, they interfere with antigen presentation, they create immunosuppression and when the immune system sees the cancer and fights it, it shows here that they are very few lymphatic metastasis.
So the concept is, is that the immune system needs help, it needs a kick start. And Dan already shows this idea -- this slide, but the point is, is that the Lm AXAL is injected with HPV antigen. So we’re going to hear here from Dr. Huh, about 265, but post this year this is the ASCO poster we're going to hear about combining it with Durvalumab and then I want to finish with my third point. I told about the virus, the disease of the study.
The Phase 3 registration study that -- we saw that Dan was talking about is called AIM2CERV with these patients where the cancers are too large for hysterectomy, they are patients with positive nodes, we know who is going to recur. We do clinical trials where the events are high. So its early stage but positive nodes at any advanced stage even if the nodes are negative. Those big cancers have a high risk of recurrence and certainly any stage that has aortic nodes. And this is a global study 150 sites in 20 countries supported by the gynecology oncology group as well as many other countries taking patients they can treat with radiation and chemotherapy because it’s -- the cancers are too large for a hysterectomy, randomizing them to control and then eight doses of AXAL over one year with the primary endpoint being progression free survival, but a key secondary end point of overall survival.
So this is a slide that Dan already have reviewed, we have maximum clinical impact here, 265 and ultimately Phase 3 trial, AIM2CERV. The Phase 3, I didn’t go through it, you'll hear about it in a little bit more detail, it's tolerable, causes an acute drop in blood pressure which are easily managed. We're going to hear about anal cancer and it's all about immunity.
So thank you for having me, we're going to have a panel discussion after our next two speakers. Thank you.
Good afternoon, I’d like to thanks Dan and Greg and Advaxis for the [audio gap]. I have the unique privilege of talking about the GOG-265 which is a cooperative huge study that was started with GOG now which is the part of the NRG and so some of the slides in the beginning of my presentation would be a little repetitive, but I think it will set the framework of what is relevant about the particular trial. And as Dr. Monk has talked about worldwide HPV related malignancies continuing to be a significant problem, I will say that it's actually grossly underreported as per the World Health Organization.
So even though we talk about a 0.5 million new cases and 0.25 million new deaths per year in reality these numbers are actually on the low side. And so in terms of mortality [ph] continues to be an issue, it continues to be an issues worldwide, it also continues to be an issue in the United States and as you will see for those women that have recurrence cervical cancer, unfortunately the overwhelming majority of these women will unfortunately die from their disease.
But thankfully the majority of women at least in this country are diagnosed with stage 1 or stage 2 disease, and obviously not surprising these patients have a much bigger outcome. The things that we are concerned about particularly are women with stage 3 and stage 4 malignancies, these women as Dr. Monk had mentioned are at higher risk for recurrence or having a lymphadenopathy and as a consequence there is a unique opportunity for us to allow improve patient survival.
So this is sort of the general algorithm in how we treat women for cervical cancer. Women with early stage disease typically stage 1 are generally treated with surgery i.e. generally a radical hysterectomy as Dr. Monk said, everybody else in general is treated with radiation combined with concurrent chemotherapy and we have other treatment options for the recurrence setting, but what I want to point out is that the women that have recurrent disease, there are generally only two major treatment options for these patients. One is public exoneration, which is an excerptive surgery where we removed the bladder, the rectum, the female organ and craniotomy and diverting urostomy in these patients. Thankfully it's actually a procedure that we do less and less of in 2016, but it’s not surprisingly it's a life changing surgery and it can actually have horrific outcomes.
The other treatment modality is palliative chemotherapy and I actually want to stress towards palliative because as an oncologist or anyone that treats women with recurrent cervical cancer, this is generally a disease that unfortunately cannot be salvaged with chemotherapy. The overwhelming majority I would say at least 99% of patients die from the disease. We might extend them their survival by three or four months we might improve their quality of life slightly, but in general these women unfortunately don’t have all their responses and ultimately succumb from the cervical cancer.
When we look at 12 month survival rates and I am going to kind of talk about why we pick 12 months in patients who’ve been pretreated with recurrent cervical cancer, this is the general Gynecologic Oncologic Group experience and for those that are not familiar with the GOG, the GOG was the major cooperative group that basically funded some of the most pivotal trials related to gynecological legacies in the area of cervix, endometrium and ovary. And as you can see here generally the 12 month survival rate from various lines of novel therapy in patients who received anywhere from no prior systemic therapy to up to two systemic therapies with no higher than 30% not great, okay, but in general the bar is at about 30%.
So I am not going to spend a lot of time on this but Dan O'Connor has already talked about the actual step-by-step modulation of the Listeria and AXAL couple of things and I deal with these issues daily with our patients, patients are obviously considering that they’re going to get Listeria, so this is a non-palliative [ph] form of Listeria, it's highly, highly immunogenic, I am going to talk about this, this is exciting and I’ll tell you why I think it's highly immunogenic.
And again I think it does a great job, in not only presenting the tumor associated to antigen, if you believe in that concept and as Dr. Monk mentioned if you’re going to take a disease, a solid organ in 2016 that going to be most amenable to immunotherapy, it's going to be [indiscernible] related malignancies, particularly cervical cancer, why because 98% to 99% of them actually will have the HPV DNA associated with them. It is the idea of solid tumor to understand the value of immunotherapy.
So in very early pre-clinical work that was done with AXAL with TC-1 cell lines, TC-1 is a cell line made by T. C. Wu, who is a pathologist and investigator, a friend of my Johns Hopkins. If you look at the general immune response as well as tumor regression and clearly they demonstrated over and over again in multiple requisite studies that we see basically tumor reduction in mice that are essentially treated with AXAL. And so the preclinical work was highly robust, was been led into subsequent clinical work.
But to kind of put this into perspective there is a trial that was conducted by Advaxis in India, actually I think it was year before even Dan O'Connor joined the Company and it's essentially an open label study that looked at women that had basically relapsed refractory cervical cancer. And these women, some of these women’s received platinum concurrently with their AXAL and what you can see from a 12 month, 18 month survival and a 24 month survival perspective that the overall survival rate was as high as 32%. And clearly what we saw there was an initial signal.
Was it a perfect study, no it's hardly a perfect study but what it did do is prevent that proof of principle and concept and clearly that maybe of some clinical value to treating patients with AXAL understanding it in recurrent cervical cancer. So to put this in further light and the recent ASCO meeting, this is from the key note trial that was recently presented, this is a pembro trial, this is the pembro trial for patients who recur cervical cancer, HPV positive, TDL-1 positive and again what we saw on the trial for overall survival was at six months is about 67% and 12 months is about 33%. But keep in mind that there were no CRs on this trial but I think that’s really important to keep in mind as you hear my presentation as well as Dr. Slomovitz’s presentation as well.
So I am going to talk a little bit about GOG-265, but there are several things about this trial I think that this group needs to be aware of because it's been an interesting journey and exercise for me personally, but we’ve learned a lot in terms of clinical trial design specifically as it relates to immunotherapy. To put this into perspective when we started this trial and correct me if I am wrong Brad but this is one of the very first immunotherapy trials period, in all of the GOG, not just for cervix and so realize that we were basically pioneers and we were just basically learning along the way and so not surprisingly we’ve had multiple amendments specifically 13 amendments because of that. The lessons learned and you’re going to see why we’ve learned from these lessons and how we created [ph], changed the trial accordingly.
So this is a recurrent cervical cancer trial, it’s a standard Simon two stage design and for those that are not familiar with that basically there’re two stages, one is the first stage we treated patients, there was a safety run in because we actually had no human experience in the United States, only in India and then the second stage which we’re actually in right now. And so I am going to present to you commercially both stages, but this is a standard Simon two stage design and we use stage in kind of two ways and I’ll highlight that. Initially, these patients had to have no more -- had to have at least receive two lines of therapy and we actually changed that midway and you’ll see that as well and they all that’s needed to have a performance status of 0 or 1 and to have measurable disease.
The one thing I do want to point out that was highly unusual. I remember these conference calls because Dr. Monk was on them originally, we talked about what the endpoint should be and traditionally the endpoints have been PFS or short OS, but we’ve set the OS at 12 months. And so -- and actually we got some pushback on that because some people thought that that bar was pretty high and in retrospect I think it was high. But in reality as I mentioned earlier all these patients are going to die from cervical cancer and so what we really want to know is how many of these women would actually be legitimately live at 12 months.
So realize that 12 months overall survival has not been the normal metric in the GOG when measured outcomes through these patients. So in terms of the actual stages so we started enrolling patients in January of 2012, the trials was about to reopen actually hopefully in the month of July. So we see two stages here, this is not the traditional assignment two stage design that I told you about earlier. Well this represents, our patients at Stage 1 who are allowed to get three treatments 28 months apart, they got in which one months later and they were pretty much done.
The Stage 2 refers to women were in an amendment we actually allowed women to get treated past through three cycles. And though these are one of the things in the lessons that we've learned from GOG-265 [ph] it makes no biologic and clinical sense, why you would just treat a patient for three cycles of this stuff. With all the other immunotherapy trials that we've learned, you basically have to treat these patients indefinitely. This trial actually allow those patients who had basically a stable disease or response to continue treatment well pass their three cycles. So that's what we referred in terms of Stage 2, and when we look at Stage 2 there are actually about four patients who received more than three doses and then there are about six patients who received less than three doses.
So on the 6th of the October 2015 that this clinical trial was placed on a FDA hold, something I'm sure that many in a room know about, it refered to a patient that with on the clinical trial who develop basically a Listeria blood culture of many-many months basically two years after her initial treatment that hold was released on December 15, so it was about two months hold, we worked through those issues, the FDA has requested some changes and as I mentioned earlier we are about to reopen that trial and it probably would be fully reopened in the months of July.
In terms of overall survival I think this is where it's really interesting. So when you look at all subjects the 12 month in terms of the primary end point the overall survival was about 38.5%, it's actually higher than we thought it was going to be. The more interestingly when you look at this patients who receive three doses, the overall survival was about 56%. So keep in mind what we are anticipating with that the survival might be even higher if patients continue to receive therapy. One of the unfortunate things in life is about timing, we were just starting to understand that before the clinical hold and unfortunately the clinical holds put a temporary break on our understanding of that, but we have no reason to believe that we won't be able to maintain the scheme expected overall response rate.
So to put these into perspective, so when you actually look at the outcomes in the survival occurs, all these other GOG/NRG recurrent cervical cancer trial that have been done over the past 15 years especially, the Black solid line puts into perspective or actually it's compared to these other trials. Okay, but you actually look at 12 months survival. I think with that Advaxis has a product that is not just clinically interesting, but very clinical interesting as you will see shortly, but clearly what we're seeing is a clinical signal that definitely merits further investigation.
So before I get into that the one thing I do wanted you to recognize is as this trial reopens and we’re going into the Stage 2 -- assignment Stage 2 past of it, the NRG and C-Tap [ph] and Advaxis have elected to basically reenroll all of the patients if Stage 2 mainly because we thought that if we continue where we left off that would introduce a bias that would actually effect the trial as well. So we are actually going to start from the very beginning which is good for us as that should give the opportunity for us to enroll those patients and give them additional therapy well after their three initial treatments.
When you actually look at the overall response rate and I’m going to talk about the complete responses that happened to be a patients in mine. We see it was pretty significant high percentage of women with stable disease obviously you can see progressive disease unfortunately we did have a fair number of patients were non-evaluable and lot of this is basically based on the fact that as we were learning about this trial we were dealing with certain toxicities as you will see in a second.
Now in terms of toxicities, I will tell you that having given the drug personally myself to patients within about 15 minutes to 30 minutes patients have a pretty dramatic physiologic response and at which you know that patients are getting something. What happens within 15 minutes or 30 minutes they develop what’s known as a cytokinetic release syndrome, they get hypertensive, they have phyrexia they have rigors, they even then hypotension sometimes and that's just sort of the clinical constellation of basically there responding to the Listeria. Thankfully it only lasts for about an hours or two hours and most patients do fine. Unfortunately there were some patients very early on that probably elected to admit to the hospital, they give them IV fluid, but all of those patients went home within 24 hours. So it's a pretty dramatic response and something we don’t typically see with our cytotoxic chemotherapies and our other Immunotherapeutic agents.
So group and I want to just talk about this patient of mine whose is actually on the trials. She is actually on this poster, this is a patient who actually lives in Orlando came to see me because she was specially interested in GOG-265, she’s 56 we’ve diagnosed her at an early stage cervical cancer, explained us all histology, kind of read back it was directly 2007 and subsequently develop a public recurrence seven years later. She got chemotherapies, you've got some additional RT, completed all of the therapy in August of 2014 then elected to enroll into GOG-265 in June of 2015.
So the following is and I don’t know how well you guys can see this from the back there, but this her initial enrollment head CT and what she had was fairly significant para aortic adenopathy, in which we are not a physician, you can see the black there, that's not meant to be there. And so as we treated here overtime and mind you that she finished her therapy around September, she started demonstrating dramatic resolution of her disease and then most recently -- actually in the month of May that this is her most recent PET scan it was in our institution and again she has complete resolution of her adenopathy. It’s a pretty dramatic response and this is actually a patient who never got the additional therapies. She just got the three, she was demonstrating a partial response and then we were going to treat her additionally, but had to stop because of the FDA clinical hold.
We do not see responses of this nature ever is cervical cancer, of this dramatic nature, and clearly something was going to gone here I think it turning to next step and this is list of things I’ll try [indiscernible], we are defiantly going to get her tissue with HPV subtyping to understand as she is 60, though she may not be 60, which will be actually be the more clinically interesting to disprove [ph], but this is really a great example. And this nation is actually about to get retreated in the month of July as well. We actually bought a [indiscernible] so that IND could be treated, she had to come off the clinical trial because they FDA hold.
To get to the conclusion, actually it's really -- in terms of well tolerated. I know this is really subjective evidence and so I think it's important to say, when our program seeing that other side who have treated patients with recurrent cervical cancer with AXAL is the subjected nature and have great they feel after they get treated. It's a common theme that a lot of the investigators report over and over again. It's kind of hard to measure on an AE scale how great a patient feels but routinely patients are measuring it over and over again, approximately 39%, 12 month overall survival rate and so I think it's clinically impressive.
Again I think this really justifies us going forward, as I mentioned we’re going to reenroll all Stage 2 patients, keep in mind that a lot has changed in the last five years, what is changed is obviously a lot of patients, the majority of that 80% and this patients have received death. And this is the changing culture of how we treat cervical cancer, so the patient population we treat in 2016 is very different when we started it in 2011 and 2012. And as Brad mentioned, what’s about to open is a huge international trial called AIM2CERV that’s looking at use of [indiscernible] actual in the study of high risk locally advanced cervical cancer.
So that will be it for me, I’ll be happy to take any questions. And thank you very much for the opportunity, appreciated.
Let me thank Dan and Greg and Advaxis for wanting me to come and present, it’s something that’s similar Brad and to Warner, we are very passionate about it and we need to come up with better ways to treat cervical cancer and we truthfully feel that there is an opportunity here and for me it's very exciting. So I think the first Brad did an excellent job focusing on the disease, Warner has really phenomenal data on a single agent activity. The purpose of this focus is to really review some of the pre-clinical rational behind using AXAL with one of the PD-1 and to share our case with you that in our view is really worthy of being singled out.
Here are some numbers that we are familiar with, but just to go through it again. We know that HPV-associate cancers are prevalent and it can be aggressive, worldwide cervical cancers is a problem and the numbers here in the U.S. are decreasing due to screening efforts, we still need to get better at screening, we still need to get better at vaccinating boys and girls as Brad mentioned, but worldwide there is still 530,000 new cases of cervical cancer. And we can see the in a general cancers other than cervical cancers are prevalent worldwide and really the head and neck cancers are something that we’re becoming more and more aware of. Over 550,000 cases worldwide. And that’s really just a term for several different disease types for cancers and cancers that Oral Cavity and Larynx are heavily good for HPV.
There is an increase in prevalence as you could see on the slides on the -- you can see increasing prevalence of the Oropharynx cancers in HPV and fortunately rates of cervical cancer are decreasing. A key number here 80%, 80% of HPV cancers are -- are HPV related. As an insider reminds me of when Michael Douglas was diagnosed and he gave his reasons why he thought he was diagnosed. I was the doctor at that time and I got called by the Daily News on a Sunday afternoon to comment on it and I differed comment at that time, which was the right thing.
But we are learning now, 80% of cancer is Oropharynx cancer are due to HPV, a tremendously high percentage. So cervical cancers though the rates are decreasing from early diagnosis -- because early diagnosis and treating of the pre-invasive lesions. We are not seeing the effect yet of the HPV vaccination and giving the real abysmal rate of acceptance of the HPV vaccination, we are not going to see the effect of that for long. Those cases are do occur are typically aggressive.
And my only other comment here is we are becoming more of a homogeneous population in Miami as Brad showed on his slide early, we see a lot of cases in Florida, it's -- Miami is an international city, New York is an international city. We are seeing a lot of people not only from developed nation, but developing nation immigrating to the United States and we are seeing a lot of case of cervical cancer, so those individuals need to do a better job in treating them.
What about Durva? What about the PD-L1 and Phase I that we've looked? Study 1108 being with its 62 patients and they divide their analysis by PD-L1 positive or PD-L1 negative tumors, overall response rate was 11% the PD-L1 positive the response rate was 18% but even if it was negative there was an 8% response. So, showing that there're some single agent activity and the treatment related adverse events of 34% none of them were grade four.
This slide looks at some of the changes that we've see in the tumor microenvironment this shows the result of the study presented at AACR in 2016, there is a window of opportunity studying neck cancers, it showed that actual induced changes in key cell infiltration and checking expression in tumor microenvironment. We could see here there is an increase in the CD8 positive T-cells and a decrease in PD-L1 between the pre treatment and the post treatment dose of Advaxis. Generally there is an increase in lymphocyte infiltration between pre treatment and post treatment. The side effects included vomiting and hypertension there were no AEs greater than three, detection of HPV E6/E7 specific T-cell response in peripheral blood and there are potential AXAL-induced changes in tumor microenvironment.
On the Phase I there was a Phase I study newly diagnosed HPV squamous cell carcinoma of the oropharynx, eight patients treated to determine the tolerability immunogenicity of the drugs. Here is a pre-clinical study looking at the rationale for combining the Advaxis AXAL within anti PD-1, PD-L1 and you could see from these pre-clinical models that the there was some activity of the Listeria by itself or was the PD-1 by itself, however there was definitely an additive if not synergistic effect when combining the AXAL with the anti-PD-1. Similarly, in the tumor model in our tumor model response we see some activity when looking at each agent by itself, but sort -- and additive if not logistical response when we combine the two drugs.
I wanted to show this similar slide by really wanted to highlight this, it's the key note data that was presented at ASCO couple of weeks ago monotherapy and cervical cancer there were no CRs in this group. We do feel that, I feel that there is evidence that shows that PD-1 works in this population, however we are not in the results of this study are relatively modest the PFS at six months 21% 12 months of PFS 8% overall survival 67% and 33% there is a signal that we need to do more 13% of the patients had stable disease. The AEs in study was consistent with the established profile for pembro.
So here is a study that I’m leading the investigation on its Phase I study of their current perception med-effects [ph] HPV+ and neck cancers the patient characteristics they require diagnosis of cervical cancer or HPV+ squamous cell carcinoma of the head and neck with measurable and/or evaluable disease. We know that most cervical cancers are HPV+ so it didn't require that inclusion.
The patients require a good performance status and no diagnosis at the immunotherapy, in the Part 1 of the study the dose finding study they require the normal 6-12 patients afterwards there was two expanded cohorts, one planned for the head and neck cohort with 20 patients and for the cervical cancer cohort of 90 patients. The first patient cohort enrollment was completed in first quarter of 2016, Part 1 second patient cohort enrollment complete for 2016 there were 11 patients in the first cohorts, in the first two cohorts, sorry. The Part 1 expansion and Part 2 expansion are open to full and estimated to further patients this summer. It's anticipated that study completion will be in 2018.
Here on the right as I want to go through the study, it's AXAL with Durvalumab in again same for 6-12 patients AXAL fixed dose Q 4 weeks plus the first dose was 3 mg/kg, in two weeks of dose level 1 and dose level 2, as I have mentioned again this is complete now 10 mg/kg. The expansion phases are planned in expansion there will be AXAL Durvalumab in 20 patients with having neck cancers in the cervical cancer part 2 there will be 90 patients of 1:1 randomization, half the patients will get Durvalumab alone, half the patients will get the AXAL with the Durvalumab. Primary endpoints are overall safety in Stage 1, in Stage 2 Progression-free survival and overall survival.
Now I want to take you through a case study. This again, this is just the highlight, this is an ongoing study and this patient's experience may not be typical of all patients but it is definitely impressive response that I want to share with you. This is the case of a 49 year old Asian woman with squamous cell carcinoma of the cervix diagnosed in 2011. Prior to coming on trial she had three lines of prior therapy, the first line was the Cisplatin/paclitaxel/bevacizumab she was treated with that from February 2011 to November 2011. She had persistent stable disease she was treated with Carboplatin/paclitaxel from February 2013 to July 2013. And finally, Carboplatin/paclitaxel with bevacizumab was given for persistent stable disease between January of 2015 and May in 2015.
She sought several -- she went to several major cancer centers and ultimately she came to us, she lives in Florida, about 100 miles in North of our site and she -- we enrolled her into the trial and she received her first dose on September 25, 2015 and she was in cohort one of the three 3 mg/kg of the actual attentive -- of the durvalumab attentive for the actual.
You can see the timeline here of her overdosing, where her first dose was in September 2015 of both drugs. As Warner mentioned, we experienced the frustration of the clinical hold, which she you continue to receive the durvalumab after the clinical hold we know at the moment. We have during the durvalumab there is a partially response noted in November 2015 and I’ll show images covert in PR with further decreasing size in January of 2016.
In March of 2016, he had ongoing partially responses and further decreasing size. We reinitiated on the therapy in March. Most recently it stands in May, confirmed a complete response with no evidence of the disease. This Advaxis was well tolerated in this patient with Grade 1 toxicities of fatigue, fever and nausea, vomiting, headache and hypertension and only one Grade 2 types of [indiscernible].
Here is imaging that I want to share from two the Target Lesion. Typically with cervical cancer we look at the periaortic nodes and what Warner had shown. Here is periaortic node which is a target and prior to treatment, we did have a confirmed lymph node biopsy, the ancillary node which I’ll show with you in the next images of the cervical cancer.
From September to January 2016, we could see a significant decrease in size of the lesion continue to get smaller and finally it was rather a complete response with no disease there. Lesion 1, the axillary lymph nodes, which again this was biopsied prior to treatment to confirm cervical cancer, a sizeable lymph node here. Shrinkage over the course of the study and finally a complete response confirmed in May of 2016. Of note we do have a more recent image -- these are the most recent images, which confirm the complete response.
So our preliminary findings were the combination AXAL and durvalumab was well generally well tolerated. The AE profile to date is consistent with the established tolerability profile of both agents. Although early in the clinical study, there is some evidence of potential synergy between AXAL and durvalumab. Evidence of activity after cycle 1 in case study with durvalumab at the dose is 3 milligrams per kilogram. The partial response converted to durable CR following resumption of AXAL treatments. Stage 2 is now open. Thank you for your time.
Will you guys now like to open the floor up for any questions on to the presenters of the cervical cancer actual background? Do we have any questions?
Q - Unidentified Analyst
On the complete durvalumab study was the patient stable disease [audio gap] after the recent -- continue or was it a study decline to CR over the whole timeframe?
Unidentified Company Representative
Once enrolled the patient received one dose of the AXAL with the durvalumab and after the 1 dose, we did see a PR, it was a stable PR through the course of the hold and then that continued to a CR after she began re-dosing with the AXAL.
Hi, John [indiscernible]. I was just wondering, if in cervical cancer, because this HPV and the patients have been exposed for a long period of time, do these patients already have existing immune cells against HPV? And I’m not sure if it’s related, immune surveillance studies due to look, see if there is any like CD8 positive HPV as present. If they do have them, does the vaccination boosts that or to the effects that you see with AXAL, because that actually point to more that tumor immune effects of the total therapy.
Unidentified Company Representative
So the question is, I guess they wanted to repeat the question for the [indiscernible] people that is there any pre-existing immunity that might be augmented or boosted with AXAL. I’ll play for the accumulate side, but we know at these studies is that only about 15% of patients actually mount a human antibody response to a proceeding HPV Infection and much of that is not protective. We know that based of the prophylactic HPV vaccine trials.
Your question about whether or not there is related T-cell effect, I think that’s one of the questions I think people are trying to answer is, are you trying to augment something that's already there or are you -- just like the PD-1 story are you just releasing the brace on something or both. I personally don’t have the answer to the question, but it's definitely in my opinion not tumorly [ph] related at all, because definitely I think there's a T-cell mediated effect for sure.
Unidentified Company Representative
I mean there're basically four situations here, right, so, there's still yes/no, and then there's basically PD-1 yes/no sort of immuno [technical difficulty]. So that creates a two by two table for our option. So, the bottom line is that cervical cancer has some heterogeneity like all tumors and the patients that have the best response are the ones we tell that have also PD-1. So these sorts of biomarker questions are not completely understood in cervical cancer, we're working on it.
And the [audio gap] same level of serious response and the second and subsequent doses or does it moderate as you give subsequent doses?
Unidentified Company Representative
So the question is, is the cytokine release syndrome that we see after administration, attenuated or moderated after the first dose, or is it the same. I will tell you that in general it's the same, what's different is the anticipation of that's going to happen. You might pre-medicate the patient differently by giving him additional IV fluid, but I don't think there's a natural physiologic attenuation of that response, it's pretty consistent throughout three, and by the third one the patient pretty much knows what to brace for basically and the nerves know right and all of the studies now have three hydrations.
Right, yes, that's right, yes. It’s been under of 100%, 75 that it's pretty much the same, so.
Do you anticipate durable disease control in those patients who achieved SD only, and if the answer is yes, do you have any data to back this up?
Unidentified Company Representative
In the 265 trial it was not -- the clinical benefit was not driven by just those that had tumor shrinkage. So, the stable disease, the durable tumor control, the stable disease if you will is what drives that 38%, one year survival rate. So, yes we do anticipate and that's why response rate is not the appropriate employing for these sort of trials and quite frankly for any immunotherapy trial its durable tumor control which ultimately ideally translates into survival. So, yes.
So, I mean actually I was remising out during my presentation, but one thing that we changed on 265 is that we went from a traditional resist criteria, IR resist as a matter of fact, let me just show you the slide, so I think it's really important. So, this is the reason we changed to IR resist, for those who're familiar with this is because what we know and this kind of partially answers your question is that many patients will have also progression of their disease before they amount an actual documented response and this is the deep [ph] experience.
And deep experience was that not frequently that you would have actually tumor swelling, not actual tumor progression, but swelling and then following that and you can see a way from top or bottom screening for week 12, for week 16 for week 72 whereby under traditional resist you would boot those patients out and then when you repeat their imaging which is what we allow on 265, in week 16 you'd then see a response.
So, I’ve learned my fears on trials like this is that we're may mean less so now, but when we start these trial initiatives that we were kicking our patients too early and calling them failures when they were not failures so, a similar message could be applied to patients with stable disease as well. Though I can’t tell you that we have lots of great examples to answer your questions, no we don't but we do on other immunotherapy trial that this is a really important example to understand, get again how our understanding of these trials and responses evolve over time.
[Technical difficulty] be announcing two CRs from the cervical AXAL regimen, based upon all of your find experience is this common to see CRs in place one areas of the study now?
Unidentified Company Representative
That's the great question, that's the ultimate question. The -- Brad and I were having a conversation inside earlier, we don't see this, we don't see patients who have recurrent cervical cancers alive for more than more than 12 months after the diagnosis returns. The care is part of the initial plan for a newly recurrent cervical cancer patient knowing of course for those patients.
So, the response rates aside which we don't have the ultimate data on yet, the fact that we're seeing some responders with CR with relatively tolerable side effects is in our view practice oncologist in the trends something that we -- is very exciting.
Unidentified Company Representative
Thank you. Okay we're going to take literally a two minute break to just let this group of panelist de-assemble and assemble our next panelist which will be Dr. Kachnic with anal cancer presentation and then Dr. Stein with the evac of PSA prostate presentation, so feel free to. We're going to go on hold to those who on webcast for two minutes, take a stretch, get a cup of coffee and we will be right back. Thank you.
Okay, thank you. It’s my great pleasure to welcome Dr. Lisa Kachnic to the podium for her anal cancer and AXAL presentation. Thank you, Lisa.
Thank you. Now that I’m a national I’ve been trying say [indiscernible], but I can’t do it yet, so you all have heard about the exciting role of AXAL and immunotherapy in cervical cancer and a bit more on oropharyngeal cancer, so now I will share with you some emerging data in anal cancer. So compare -- well I mean all the cancer needs you’ve heard cervical I would say sort of medium in terms of its numbers or oropharyngeal more, but anal on the totality of these three cancers is much rarer.
In 2016 about 8,000 individuals were diagnosed with anal cancer, more women than men and this led to over 1,000 estimated deaths. Now when I spoke about anal cancer let’s just say 15 years ago, I can remember at the change of slide almost every year and update it, it was about 4,000 individuals. So although anal cancer is a rare disease the cases have been increasing every year and now we know it's due to HPV.
So we hear the story again HPV is not just cervical but it's also for anal cancer. We always thought it was as like Dr. Monk said earlier promiscuous women, promiscuous men, than we thought HIV was the cause, but now we really know it's HPV and in those we are immuno-suppressed because anal cancer is relatively rare disease we’ve really had a limited research focus so it's very exciting to have the support here to do some much needed work.
So he is just a sample of the OCC and guidelines for anal cancer, not much going on here you can see from metastatic I am actually going to share with you, there is not really a standard, but with really very low level of evidence we use [indiscernible] and platinum. For localized cancer, we do have level one evidence for radiation Capecitabine and Mitomycin C and low level that in the substitute that five of you would keep Capecitabine, a small Phase 2, 20 person study from the UK in fact.
So to start just to show you the evidence from metastatic disease and again there is none, ther is no standard, so when a patient progresses from local disease to metastatic or presents with metastatic disease typically we’ve used [indiscernible] and platinum, but really not based on anything except for large theories and by large I mean about 30 to 60 patients.
So interestingly enough the NCI a few years back recognized that the rare cancers and again anal cancer is a rare cancer, we need a bigger forum to try to establish standards of care and to perform research. So they established their international rare cancer initiative and this is anal cancer’s first trial on a man approach and basically it's a small Phase 2 randomized trial that looks at -- not really the standard, but what was being used of platinum and [indiscernible] versus carbo and taxel. And the treatment is given for about six months and be continued at the discretion of the investigators. It does include HIV+ patients and they are stratified for that; they are also stratified for HPV status and prior radiations. And then looking at primary endpoint best response and at every three months the CT scans for RECIST criteria to look a response is being performed. And as I mentioned, the small, only 80 study patients I first opened in the UK; it just opened in the U.S. and it's about half way to completed. And based on this, hopefully we’ll at least establish, based on a small study although randomized, a standard that then we incorporate immunotherapy or other therapies.
So what about localized disease? So, this may sound boring, but we've been doing the same thing, although based on level-one evidence since the 1980s. So, before I even became a radiation oncologist, radiation, 5-fluorouracil, mitomycin was the standard of care, based on these trials shown on the slide. And really, these trials we’re just trying to determine because 5-fluorouracil, mitomycin really has some very sort of poorly tolerated acute side effects. What were the components that were necessary to get the best response, and we found that what initially was thought by the few mitomycin in addition to the radiation really gave the best response in terms of local control and a little bit towards colostomy for free survival. And since that was established a standard, we had some attempts to improve outcomes for localized disease. But, I have to say these attempts really have gone nowhere, and I'll share with you the trials. The first that we are going to look at those upfront and outback chemotherapies.
So, the first trail was one that I helped with through the RTOG and this was 98-11. And patients that had local disease and these were tumors that were over 2 cm in size and they were node-positive but not metastatic, and since it was an earlier trial, no HIV patients were included. And their standard, as I mentioned, was five and a half weeks of daily Monday to Friday radiation therapy with two cycles of 5-FU and mitomycin C. And this study was started late in the late 90s and in the early 2000. So, the radiation that we gave at that time were sort of the big box CCLs [ph] from a front and back two dimensional the abnormal tissues coming out the same as the tumor does.
And the experiment on this randomize Phase 3 was a little bit different, not the best design trial. So, they were looking really to get better outcome but also to spare the toxicity of the mitomycin Sales by replacing the mitomycin with a platinum. And platinum is also a DNA double stranded cross link attacker. So, they thought it was good and act the same. And pilot study showed that it did. However, the pilot studies had to run in of two cycles of finest even platinum before that substitution of the platinum for the mitomycin C. So, maybe not the best design but that's what it was. And so the primary hypothesis on this trial was that the substitution and in run of the platinum would increase five year disease free survival. And guess what? That’s not what we found. In fact that running of the platinum inside the hue and that substitution was poor survival.
So, these are the updated results not from the original publication. And the original publication showed the platinum arm to be worst in terms of the local control but now we actually see it worst in survival as well. So, you can see p value is really significant for decreased disease free survival with that platinum. So, we also see poor local control; we see increased colostomy from local occurrences and overall survival was significantly poorer with the platinum. So, giving more chemo upfront did not work.
So, the UK actually did the better design trial because they did it two-by-two randomization. The first one was to look at that substitution of platinum and the second one was to actually look at the addition of more chemo, in this case out back chemo but also 5-FU and platinum. So, for the first randomization, the primary endpoint, which I already said was a little bit lumpy because it's hard to show, was that platinum substitution would give a 5% increase in clinical complete response at six months. And then the secondary -- and the second randomization, primary endpoint was that just outback chemo therapy would improve progression free survival and there was a follow up of five years.
So, if we look out the outcomes of this trial for that first randomization, you can see at six months, the clinical complete response which is a bit subjective, is identical for the arms. And then, if we look at the second randomization, surprisingly the numbers were almost spot on for three-year survival, 73% in the planned arm and 74% in the mitomycin arm. So, a negative trial not showing any benefit of the substitution of platinum but more importantly giving more cumulative therapy.
So, I have one more data set to share, it's not been published yet, so I’d just provide you with preliminary data from our previous presentation at ASCO. And this is looking at 5-FU platinum and radiation backbone for both HIV positive patients, and that’s the AMC or AIDS portion or for immunocompetent patients and that’s on the ECOG trial with cetuximab. So, 5-FU platinum instead of mitomycin C, it was at the time at RTOG 98-11was in its final phase of enrollment, so they decided to use the platinum thinking that study would be positive and then added cetuximab. Two small Phase 2 studies and they gave about six to eight doses of cetuximab with kind of the standard chemoradiation, in this case platinum. One thing I would mention though that the ECOG trial gave that running on platinum and 5-FU 2 which makes it pretty hard to running [ph] safer. But their primary endpoint was to see if the addition of cetuximab would reduce local reoccurrence.
And we do have little bit of data to share on this trial but again preliminary and two-year data and that was that the locoregional occurrence was 7% on age trials on the HIV patients and 13% on the ECOG trial. However, although results may be interesting in very small population, the pharma company for cetuximab, I can tell you panitumumab and so on really don’t want to support a study for rare cancers.
So now, I am going to just show you what locally advanced anal cancer really has great outcomes because we think that the chemoradiation has a really good local control and patients are cured to the highest level, and that’s not the case. So, when I actually took the RTOG 98-11 data and we had almost 600 patients on that trial, and I heaved out each of the stages of disease, it wasn’t just the node-positive or those big tumors that had poor outcomes; it was the stage T2 node-negative patients. And it's a busy slide, so I summarize the result on the next slide.
And it shows five-year disease free survival, so what I call kind of really a locally advanced anal cancer to be 45% for those T4s. So, those are tumors that are embedding adjacent structures. Only 59% for T3s; those are tumors that are bigger than 5 cm. And even if you have T4 tumor, you have a larger one, 40% of those are going to recur, so not that good. And then, if you are node-positive, you really only control about half the patients. So, there is opportunity for improvement.
So, how can we fill this unmet need? I think immunotherapy has a great potential for anal cancer as well. And you sort of heard the story already with the PD-1 inhibitor and the vaccine therapy. So, radiation itself can also potentiate the immune system. So, having kind of immunotherapy and radiation although not quite yet understanding the sequence of events that we should most properly use is very exciting for anal cancer.
So now, I am just going to share with you some of the early trials for both metastatic as well as local anal cancer, and we are going to start with NCI trial that was presented recently at ASCO, the PI is one of my dear friends who I work with kind of that all level in the corporative group in the NCI Cathy Eng from MD Anderson. So, she presented her study on nivo and metastatic anal cancer at ASCO and this was a Phase 2 study. At the time of ASCO, it just finished enrollment of 37 patients but about six patients were still receiving nivo [ph] therapy. And these were patients that have had at least one, if not more prior therapies for their metastatic anal cancer and no prior immunotherapy. And the results were quite good. About half the patients had either a stable disease and then two patients had a complete response with seven having a partial response. Again, these are 37 patients and 34 were valuable. So, median. The medium progression free survival was 3.9 months. It's highly important to note that this was I think the first immuno trial that actually included some immuno compromised patients. I believe there were two HIV+ patients and a few patients that had HEP B or HEP C. And then, this trial, as I mentioned, is a few patients still receiving their nivo before it completely closes, but they are taking the next stage might be to combine nivo with another form of the immunotherapy.
And then the second trial that I wanted to present in metastatic anal cancer is with the Advaxis vaccine and that should be starting to recruit soon. And this is now I call more of a Stage 1 T study. And this is where treatment naïve metastatic patients are those that have progressed after platinum therapy and they are going to receive vaccine every three weeks for upto two years. The primary endpoint for the first stage will be overall response rate and then it will be six-month progression free survival and then the first stage safety and tolerability. And then the second Phase endpoints will be duration response, progression free survival and overall survival. And on the Stage 1, if you have a response rate of equal or greater than 10% or if six-month progression free survival is 25% or better, you will go onto Stage 2. For Stage 1, there is 31 patients, for Stage 2 24 additional patients and there is thought that Stage 2 may also include a checkpoint inhibitor but they will wait for their Stage 1 response to term in that. And I mentioned already the timeline is that this should be opening soon.
So, I’m a radiation oncologist, so I don’t have opportunity to see as many metastatic patients as some of the other panel members do. The next study that I will present is near and dear to my heart since this is a study I put patients on, and this is for a locally advanced anal cancer, and this was started by my good friend and colleague Howard Safran from Brown University, and again using the vaccine therapy that you've heard so much about.
Now, I briefly mentioned that radiation may also have an effect on the immune system, and this is just some of the preclinical data done on a mouse prostate cancer model to show that. And although busy, I will try to take you through the figures here, and maybe I will use the pointer for this one. So, on the Y-axis here is mean tumor volume, and this just shows array of different treatments. So, here is control; here is the vaccine alone; the green is radiation alone; and then on the whole that you combine the two or that red line, you pretty much have no tumor remaining. So, really they worked in combination or we call it the lab synergy. And then, if you take one of the mice that had a complete response and then challenge them again with tumor, you can see on the second figure here, if you had a control that mouse would just continue to get tumor. But if you actually gave tumor in a mouse that had a complete response after having the vaccine and radiation therapy, you still have no tumor growth, so pretty amazing.
So, this is the Brown study that I was talking about that's ongoing. It's a Phase 1/2 Study; the goal is 25 patients; it's for Stage 2 and 3 anal cancer; so those T2 and above. But in this case since we created it based on our knowledge from RTOG, it's for those higher risk T2, again those much bigger greater than 4 cm T2 patients. And these patients are HPV positive. And we decided again because the HIV patients especially with low CD4 count could be a little bit [indiscernible] to put on a trial like this without any prior knowledge that we would hold on from that and just had HIV negative patients for this pilot.
So, how we design this was that the patients received vaccine one dose upfront and they got the standard 5.5 weeks of 5-FU and mitomycin chemotherapy. We now have really fancy radiation technique, so that we've decreased many of those side effects although the mitomycin can really drop the count still for a little better amount with the fancy radiations, but they still made it quite a bit with the second doses of mitomycin. So, they get the 5.5 weeks. And we decided not to combine vaccine with the chemoradiation for the reason as I just mentioned, but then to give some outback vaccine, which we did for three cycles, once every 28 days. And the primary endpoint of this was six months complete response rate. And just to remind everyone, the treatment for anal cancer does not include surgery; it's strictly chemoradiation; surgery is reserved for salvage.
So, I mentioned our goal was 25 and it was based on Simon’s two-stage design and are null hypothesis was that the true response rate is 50%. And in the first stage, 16 patients will be accrued; we’ve had 11 thus far. And if there are 10 or fewer responses in these, the study would be stopped. And I don’t think that’s going to be the case, because I’ll share with you our preliminary results.
On the eligibility criteria, again, as I mentioned, these are for the bad locally advanced players. So, the larger tumors or the node-positive, and they had adequate bone marrow and renal function, and I mentioned then no HIV thus far. These are the 11 patients that were accrued thus far. You can see that male and female are about equal in distribution. Most of these were Stage 3 and about half had node involvement.
So, just to share with you our pilot outcomes. So, we have 10 patients treated and alive on the study since April 2013. As I mentioned, almost half had really the normal disease. They tolerated vaccine very well, they had acute grade 3 flu-like symptoms most in most patients -- half patients; it was done in 24 hours however. And there was one patient, the 11 with cardiac event from 5-FU that was unrelated to vaccine.
It’s really important to note that that first cycle of vaccine therapy did not worsen the chemoradiation toxicity profile over what we know from all the patients that we’ve accrued to the RTOG studies. And those 10 patients that were treated, all experienced clinical complete response, which is very good. We’ve had one recurrence to date at 10 months post-treatment, but I will show on our next slide that just about all of the patients are out two years or longer now, so that’s very good.
If I look at early local failures for those patients that I showed you on that busy slide of all of our failures from the RTOG study, about 60% of the patients in aggregate failed at about two years. And about 90% of all the failures are by two years. So, for our patients here being out two years is an important time point to show that we’re seeing durable responses with this vaccine therapy. And slide just shows you the individual patients in that. And you can see that further majority of patients who either are approaching our past two years. And this was a patient who expired unrelated to the study treatment, and this is a patient I mentioned that progressed systemically, although locally they were controlled.
So, really based on the very exciting cervical data and this early pilot data, the RTOG now under the NRG umbrella was really interested in pursuing a Phase 2-3 trial with the same approach that I showed you in the Brown University schema to really see if we can challenge and change the standard of care for this disease with vaccine therapy. So hypothesis was that with the vaccine therapy, we could decrease really high locoregional failure rate and increase disease free survival compared to that 5-FU mitomycin and fancy radiation IMRT alone.
So, our Phase 2 randomized primary objective was to reduce locoregional failure, when added to standard chemoradiation and the Phase 3, if we got a signal from the Phase 2 was really looking at disease free survival.
If we look at the secondary objective, overall survivals are important ones; we saw that in the metastatic cervical cancer study. Overall survival was quite high compared to historical controls. So, we wanted to look at that on the anal study as well.
We’ll look at adverse events, probably most importantly we have the same question that you do and we would definitely profile the T-cell repertoire with each stage of our treatment here by both the arm collection and biopsy to understand, which patients respond and why. And then, we also have some quality of life relative as well.
The eligibility criteria are exactly the same as you saw on the Brown Study. As is the schema, since that was the pilot data we had and now. Although, it will be really important for that emerging laboratory data for us to really understand the best sequences in these locally advanced trials, you saw on cervical trial that Dr. Monk presented that you’re going to get their chemoradiation upfront and then maintenance vaccine. Here with that emerging radiation data, [indiscernible] radiation oncologist I guess that put forth this trial, we thought it might be important to have a running vaccine hoping that that would kind of boost the response we see with radiation and then more vaccine outback. But, I think this is a question that’s still out there, what is the best sequence.
And just to show you that number of patients for each phase, for Phase 2, we would look at two-year local regional failure, and I told you why because when we look back at all of our patients that were on RTOG anal cancer trials, most of those local failures occur before two years. The two years are really nice early endpoints to see if we get a signal with a vaccine addition. And so, we'll be looking to see whether we can decrease two-year local regional failure from 25% down to 13%. And I showed you the five-year data which was about 50% but that's what it is two years. And then for that, we would need about a 170 patients. And the Phase 3 looking at disease free survival, we would only need additional 94 patients, so, pretty moderate size trial, 264 total, to see if we get a response with a vaccine that could change the standard of car for this disease. And just to know, if we do get local regional failure, it's not that well cured, we cured about 40% to 60% of the patients but it's not a homerun with a colostomy surgery.
So, the next steps for us and at least for localized anal cancer, we are so happy that Advaxis is part of our team to really push this trial forward. And we are under discussion right now at the Radiation Therapy Oncology Group Foundation to see it we can work together to do the Phase 3 design as an RTOG Foundation Study.
So, here's my summary. For metastatic disease, there is no standard. That international study we call it the InterAACT trial is underway. AXAL, the vaccine may be first or second line therapy depending on what we see for the outcomes of that trial that we'll begin. And there may be a role of dual immuno-inhibition with the vaccine and a checkpoint inhibitor, more to come on that. For locally advanced disease, unfortunately for all of us and our patients, radiation 5-FU and mitomycin still remains as only standard, but I showed you the local control for the larger lesions or the node-positive disease is really suboptimal. I showed you that adjuvant chemo is no benefit. They're not really looking any longer EGFR inhibition. So, looking at the data that we saw in cervical cancer today and then our anal pilot, I really believe that vaccine therapy is an encouraging way to go for this disease. And hopefully in the next couple of weeks, we'll be working closely with the Advaxis team to discuss initiating a study in the locally advanced anal population.
Thank you very much Dr. Kachnic. Would anybody like to ask any questions to Dr. Kachnic at this time?
It's either anal cancer is very boring or I covered it so clearly or you need coffee.
If there're no further questions, we'll turn the floor over to Dr. Mark Stein from the Cancer Institute of New Jersey for the Advaxis PSA talk. Thank you.
Good afternoon. Thank you all for allowing me to present today and for being the cleanout presenter. And without further adieu, I'll tell you about my interest, which is in treatment of prostate cancer really through the entire spectrum of the disease. I'm a medical oncologist. And so, what we know about prostate cancer is that, it is obviously a disease that on the one hand there's a incidence that has decreased in terms of closing mortality over time potentially due to screening, yet this is unfortunately a few of the areas our own government recommendation; some undermined some of the advances that we've made in the field and at the same time it's an ageing population where people generally are living longer. So, clearly prostate cancer still represents a substantial health burden in our society. And then there are also some of the disturbing like number of younger people who are getting more prostate cancer also, and this has sort of been well documented in several studies. And also it certainly occurs in a number of disparate populations, underserved populations of obviously a large risk in African-American men. So, prostate cancer is an important disease to focus on. And to a large extent I’ll try to convey some of this. It really represents a disease where the number of treatments that we have are relatively small and they're in many ways inadequate in the more advanced setting.
So, I want to put some numbers around this because people generally hear of prostate cancer, people die with it not from it, doesn't really close any problems anyway. And so, it's actually, it is foolish to sort of presenting numbers from years ago. What I did is a took a recent publication to actually try to project out and sort of put some numbers around the different states of the disease because prostate cancer has a relatively long natural history. And so, in fact there're many different time points at which somebody can intervene. So, this is estimated incidents in 2020 based on epidemiological trends, right estimating about 260,000 new cases of prostate cancer that will be diagnosed. Unfortunately, even with the best treatment, whether it's radiation or surgery, roughly a third of men, the ballpark figure will ultimately recur and then we found -- this we manifest by revising PSA that's a protein that’s found in the blood and that is a very sensitive marker of both disease being present and also a marker of recurrence.
You’ll see that people who then go onto recur also will be treated with androgen deprivation therapy known as a hormonal therapy or castration and then will progress through a stage where they for many years can control the disease, ultimately will then progress, become resistant to hormonal therapy and generally develop metastasis and in this stage estimates having metastatic castrate resistant prostate cancer and then there are patients who generally at that point be treated with a variety of second line therapies.
To give you a sense of sort of what the therapeutic landscape is now in prostate cancer with a localized therapy androgen treated with definitive treatment, which will be radiation therapy or prostatectomy, there are pros and cons for each one. Again, in the recurrent state, there truly is no standard of care, again somebody sort of recurrent, you can prognosticate, you can try to figure out it was a more aggressive recurrence or less aggressive recurrence. Unfortunately, the only thing that we really know works in this setting is again hormonal therapy, depleting testosterone, which has both substantial emotional, psychological, sexual and physiological consequences, so we try not to employ this too early. When it comes to patients with more advanced metastatic disease, the standard of care continue the androgen deprivation therapy, then to start to add on it different agents, which will be second line hormonal therapy that do a better job of blocking the androgen signaling access; there are drugs that are recently proven in last five years and androgen receptor blockers enzalutamide or abiraterone which block synthesis of testosterone that is impacted immune-therapy and proved in the space known as Sipuleucel and I'll talk a little bit more that in a few minutes. There is a chemotherapy approved in this areas known Docetaxel that improves median survival by roughly four months. We have a second line chemotherapy, again roughly similar orders of the magnitude, a radium which is a systemic bone directed therapy, does not target the prostate cancer directly but sort of targets the bone micro environment. And then there is a really Mitoxantrone, which is essentially improves pain but has never been shown to improve overall survival.
So unfortunately, compared to other diseases such as breast cancer, there is relative dearth of agents that have approved from the advancement that has prostate cancer despite the benefit there are an estimated 57,000 men per year that will suffer from this condition. And let me tell you that ultimately none of these treatments [indiscernible]. So, there are important unmet needs both in the advance metastatic setting and then really in terms of trying to develop therapies that are effective earlier on in the course of disease to prevent men who haven't had this, because the PSA -- this protein that we can measure in the blood indicates recurring the very early one and we don't necessarily know what to do with this early marker of recurrence.
Just to give you a sense obviously, sort of the earlier stage of diseases and survival is longer and we know that when patients have castrate resistant cancer without metastasis, median survival is approximately 45 months and this is from the study that was already done several years ago. And now more from temporary cohort of men with metastatic castration resistant prostate cancer survival, only 35 months. And the suspicion is that we would sort of look at this [indiscernible] again, we will be looking at men who roughly are living out about five years in time of castrate resistance, development of castrate resistance. So this point being sort of treat people later than obviously the time until death winds up being shorter amount of time, and we think that into consideration in designing clinical trials.
The question is and some of this has been data that you've heard already from my colleague, and we see why immunotherapy, why immunotherapy in general. And obviously the point is that with other therapies that are out there and this is particularly really clear in prostate cancer with agents that target the androgen access and androgen signaling what we essentially see here is that the standard tumor targeted therapy, patients ultimately -- they survive and they develop resistance. And so, they try to move this far out there and they really try to improve this with not just sort of current immunotherapy that might be available in prostate cancer but then to really add agents and to improve upon immunotherapy to sort of move this far up and improve the overall survival curves.
In terms of sort of benefits of vaccine versus conventional therapy, again, the idea is that you’re not just targeting a tumor you are really sort of developing an immune, treating the immune system to recognize the tumor and hopefully this provides ongoing and durable benefits so that the immune system will evolve with the tumor itself, while tumor therapy often works immediately unfortunately the immune therapy sort of has more of the wait on its side so therefore you have to take clinical challenge in choosing patients. But the same time again resistance generally is -- which is not as equivalent but it has a durable response with two immunotherapies you see that that can really last a lifetime hopefully. You also see that there are limitations also from conventional therapy in terms of toxicity while therapeutic vaccines that require an adequate immune system and often multiple agents who achieve an adequate immune response and again we’ve seen some of this discussed also.
So really the important factor when you consider immunotherapy in prostate cancer for that matter any of the tumor is that tumors have evolved and not die and in general our own body has about to not be attacked by the immune system and so there are multiple suppressive mechanisms that are on healthy tissue and poise them out of the tumor in place to evade the immune system I think this is really sort of an important team here so actually therapeutically we know that there are regulatory T-Cells and myeloid the [indiscernible] cells and then you would have the T-Cells themselves that really have again evolved so that as they don’t [indiscernible] a healthy tissue and that’s really the checkpoint at a time on the T-Cells.
And so what you can do is you can treat somebody with a drug such as we’ve heard about PD-1 inhibitors that might poise the T-Cells to become activated and yet if you still have these other sort of aspects of the immune system that can dampen the response then again you will have some actives treated but there is no response. So that is unique is not just T-Cells that are present but also T-Cells that recognize the tumor has been on it and that’s where really the importance of adding an antigen that is directed towards the T-Cells comes into play so ultimately you want to have is a treated responder where you both have unrestrained T-Cells, T-Cells that can proliferate and then you want the T-Cells to be able to generate a tumor specific response.
And mind you this is a slide that sort of comes and that is not specifically with regard to Advaxis but Advaxis really Advaxis PSA I think is so exciting because it really sort of meets all of these different criteria and is certainly the reason I’ve become so excited about this platform. The idea is that you need to train a T-Cell that T-Cells is often I think there was a question that was asked earlier, are there T-Cells that are sort of naturally in circulation that will recognize the tumors being born often what happens that T-Cells become natured they don’t necessarily recognize our own body as being foreign and what you can do is you can sort of activate them by either introducing peptides viral DNA, by introducing whole cells, a whole variety of different platforms have been used to try to train a T-Cell to recognize a tumor, and then what you need to do is figure out a way of taking this [indiscernible] cell and then using that to activate the T-Cell and then taking the T-Cell and allow that to not be shut down by the tumor. So this multi step process that needs to take place.
And as I said before T-Cells even if you activate them, even if you make them sort of recognize the tumors being foreign, the tumor that has a whole bunch of defenses and this is really the reason we show this slide is to just sort of give you a sense of how truly complicated it is and how many redundant mechanisms there are in the body, so if you look at this and say gosh it's a miracle that a T-Cell ever does anything. Unfortunately we know that particularly in the setting of the tumor this PDL-1 interaction that normally serves to dampen the interaction between the T-Cell and the tumor really seems to be a predominant mechanism of shutting down the T-Cell.
And so really this provides I would say an opportunity to stimulate the immune response and also potentially opens the [indiscernible] now that many of these different pathways have been characterized to actually potentially having not just sort of a combination with one or two agents but potentially down the road I think that we want back we seem cocktails of immune stimulants working together. But again if you don’t have the T-Cell recognized and the tumor is being foreign then a lot of these additional adjuvants may not be of consequence. And in fact really the question that I wanted to -- what we’ve done this point is why in prostate cancer what have we accomplished so far, where are we going.
And to that point I want to highlight this so there is I would say you true for principle there is in fact one agent in prostate cancer that now is that [indiscernible] system is [indiscernible] full range right and what that does. That sort of accomplishes I would say one of these first objectives, which is to really get more antigen into the body. And essentially what happens to that patient and immune cell known as the monocytes that’s collected it actually is driven off in a basin of blood bank and sent out to a laboratory where these monocytes are then allowed to mature and the monocytes are co-cultured with a protein that is specifically prostate cancer and then once this maturation takes place these monocytes mature into this dendritic cell with sort of the master antigen presenter and then that in turn stimulates these killer T-Cells and then these T-Cells go out and kill the tumor unless I'm sure it's been while that's is all really complicated but they are actually it has then things we file to some degree of efficacy which I will show, the challenge is that this is a while they are as you can see from the slide here it is a rather complicated process which involves things like aeroplanes and taking blood from one place and to another it's not an off the shelf product and again sort of although we get more antigen in, it doesn’t necessarily get rid of some of the immune suppressive aspects of the tumor itself.
And so it's proof of principle, I think that is certainly exciting as anything that can improve overall survival in prostate cancer, which believe when we have patients for long time and there are other agents such as chemotherapy and immunotherapy it is the vaccine and immunotherapy belonging survival certainly I would say encourage them into then developed other types of therapies here and this is the sort of the pivotal trial which demonstrate median survival benefit of 12.1 months in this setting. One of the paradox is this treatment is that there actually was no change in time to progression meaning people -- we file scans the scans got worse initially it looked like the drug doesn’t do anything but as we keep filing patients when you see as the people treated with it do in fact benefit overtime and then I will sort of show you a theoretical construct why this might be the case.
There is another vaccines platform that I myself have worked with the 12. PSA [indiscernible] this in fact is a known Phase 3 trial since we get a different rate of stimulating the immune system. This uses a vaccinia virus with antigen that are then injected in some of the vaccinia stimulating immune system. And so again it's another way of trying to introduce antigen and trying to stimulate the T-Cell interface two trial again it did show in a small Phase 2 trial it did show sort of only promising results again sort of yet again to just what prostate cancer is the type of tumor that can respond to immune therapy again as we saw with the other drugs no change in time to progression.
And now there is a large Phase 3 trial that we are waiting for results on and so one question which one could ask is it that these agents we are seeing that they work but they improve overall survival in people longer but why is it that the scans don’t stop about better right away and suddenly this ones have a challenge both in terms of patient care and a regulatory approval and this is what I’d care about one of our colleagues that we got from the NPI where they actually sort of looked at tumor kinetics, PSA kinetics and really modelled out and sort of shown this theoretical construct, where you can see that and typically it happens with set of toxic chemotherapy and as we administrate it the tumor burden goes down, patients become resistant and then ultimately and unfortunately some into comes to disease and as oppose to what happen with that treatment overall point to that get signs away.
So what happens is that immunotherapy typically we think one this is in -- again you sort of [indiscernible] maybe as a single agent by itself what we've seen with some of the other immunotherapies that has been approved is that what they seem to do has is slowdown the overall progression, so while there might not be a rapid decrease in tumor burden there seems to be the sort of general delay in tumor growth. And again this is sort of studies have already been published and this model is derived from that. And therefore what one might see is sort of early progression, but yet to sort of slowing down of tumor growth, and then what would hope is that if you can actually combine the vaccine with other agents that might improve efficacy then you actually might sort of get to the point where you both decrease in tumor burden and this progression overtime will never reach sort of that rational where you will see radiographic progression and clearly you will improve overall survival. So this is sort of the model that is under immunotherapy and prostate cancer that we’re trying to work on and to develop and to get from at this point here to that there that ultimately could be fixed combinations that would really improve overall survival and sure.
So, as I said there are certainly several different agents that are out there, there are other sort of small biotechs that are using prostate drug antigens with different vectors that are trying to show some evidence in early files this is published at ASCO sort of one idea but again certainly not really combining their platform with a second check point inhibitor yet there are trials with other check point inhibitor such as ipilimumab and some of you are very familiar with the work in prostate cancer and there was actually a Phase 3 trial that was done with ipilimumab that is a check point inhibitor in prostate cancer and although gain there was sort of encouraging evidence of the activity in ipilimumab unfortunately the large Phase 3 trial round up ipilimumab as single agent impacted cancer wound up being a negative trial. But again there you've sort of achieving the check point inhibitor you are de-repressing the T-Cell but you are not providing an antigen. And then there was also a Phase 1 study with nivolumab which is a PD-1 inhibitor and which was done in all style tumours but unfortunately in the 17 patients that were treated with prostate cancer no responses were seen and this in fact as been the topic of a lot of discussion why is it that PD-1 by itself doesn’t work in every tumor and due for that matter why doesn’t it work by itself in prostate cancer.
And so maybe since some of you might ask that question off, certainly one thing that seems to be an important factor in determining whether or not a tumor responds is in some cases it could be that you have to have something that the immune system recognizes in anal cancer and head and neck cancer the effect that there is a HPV virus often there is something that allows the immune system to recognize the tumor is being of a foreign origin, often we know that tumors have seem to respond to check point inhibitors have a large amount of DNA damage and though normally that often might be related to sun damage and other tumors such as lung cancer might be smoking damage prostate cancer is a whole as a relative these all [indiscernible] mutations and therefore by itself check point inhibitors don’t seem to be effective in prostate cancer, which is then mean to meet you sort of obviously the rationale piece of respire system and you have seen this slide before.
I really what I’d like to sort of highlight here is that the versatility of this platform is that you can [indiscernible] with [indiscernible] you can sort of put in your particular antigen you have, the company has put in the antigen of interest in this case PSA of prostates fitting antigen is an evolves characterize antigen that in fact is specific to prostate tumor it doesn’t [indiscernible] with other proteins in the body and is an effective way that we have seen that we can actually activate T-Cells to attract tumor. And so just to take you through right this with Syria obviously a -- it goes both into the antigen presenting cell as you carry this can get into the [indiscernible] wall, it can be presented activate the T-Cell and then with T-Cells and then go ahead at the tumor but at the same time diminishing being the biologic [indiscernible] suppressive cells and in regulatory T-Cells that create an unfavorable environment for tumor response.
And so there is very good preclinical data that shows that compare to other platforms that I have sort of already discussed that shows the vaccine in PSA based platform that used in [indiscernible] on PSA construct there is a delay in time to growth in tumors in mice treated with this. And then there is additional pre-clinical data that show that this construct does in fact deep treats the regulatory T-Cell contact. So really these sort of while increasing CDA positive killer T-Cell. So in the pre-clinical data the single agent again without heading an immune check point inhibitor, we see evidence pre-clinically that there is the way in time to tumor growth using the -- and that is PSA platform.
And then I reckon that actually this is highlighted and it is an impressive work looking at the vaccine plus for instance on radiation. Where again the radiation has been known to induce inflammatory environment and get rid of a number of the immune suppressive facts of the tumor microenvironment and so we see here that there has been a pre-clinical evidence of synergy when radiation is combined with this vaccine and that’s potentially a development platform that one can use when radiation is appropriate and I’ll discuss that in a few minutes.
So really, I would say where you have already heard about obviously it is very-very impressive about poster and it's really relative to prostate cancer as well, that there is an important rationale both combining with the [indiscernible] technology with immune check point inhibitors. And again you are both activating the T-Cell and then you are preventing the tumor from blocking this interaction and inhibiting the T-Cell activity. And so this has been shown pre-clinically wher with most of the HPV related tumors where again in sort of all these different strategies can delay time to progression but the mice that are ultimately wind up leaving being cured essentially, are mice who both receive the E7 [indiscernible] plus an anti-PD-1 treatment. And then this ultimately is translatable hopefully in larger trials.
So with all that background, we are now at the point of being able to do a Phase 1/2 trial, looking at ethics of the ADI test, PSA both of the single agent initially and then in combination with Pembrolizumab which is a PD-1 inhibitor. So this study is now open and recruiting again it sort of has two parts. In Part A, we are looking at the ADXS-PSA as a normal therapy and this setting the treatment is given on a 12 week cycle with treatment on weeks one and getting to week four and the beginning of week seven and then our patients are reassessed at the end of 12 weeks, okay. And then once a safe dose of this single agent is established there has been a second Part B which is in combination with PD-1 inhibitor.
Patients in this group all have actually resistant to metastatic disease so that’s again on that continuum, they are towards the end of the -- unfortunately end of the continuum and although it's not a very heavily pretreated population it is not necessarily a tumor naïve population either these are patients who generally have been treated with few of the prostate seven therapies including chemotherapy and monotherapy or one trimuno therapy these are patients who are not so sick that they will be unlikely to benefit from immune therapy meaning they have not had more than one prior chemotherapy in the medicine.
So, sort of give you a sense of where the trial is right now. Dose level 1 while patients recruit, dose level 2 three patients and then a dose level 3 another three patients, there is a dose level, the planned expansion will now be at dose level 1 in combination with pembrolizumab. And although dose level 1 and 2 are overall was very well tolerated with really a similar type of adverse event profile to what we've seen now in much larger studies, again sort of they seem to probably go across the platform. In at dose level 3 there was both hypotension and hypertension again which you've heard about as being part of this sort of intrusion related reaction that is generally something that can be addressed at the time of treatment. That being said, there was a programmatic decision to potentially -- to predominantly focus on dose level 1 and then to use that going forward in combination and so currently we are treating some additional patients in dose level 1, to verify our sort of safety experience at this level and we will then use that data to move ahead into that with planned extension with pembrolizumab which we are hoping to see results similar to what's being seen on that board just to see the prostate cancer.
We have had patients who are on out to roughly of 3.5 months, unfortunately these patients feeling with [indiscernible] plus the clinical hold and so I think that will be important to the understanding that sense of where this as a single agent, but again may we have hope just to sort of see this move forward in the combination that would be imminent. So, the real question is sort of although I think that from a regulatory standpoint it is easiest to get approval when a drug is developed at this relatively late stage obviously unfortunately these patients will progress to include the rest of the therapies and ultimately die from their disease and therefore something like overall survival it is an endpoint that is all sorts of using to achieve one really would hope that there is a good data looking at potentially synergy and all of these disease settings and it is the appeal as a whole of prostate cancer is now starting to recognize the importance of moving therapy earlier the FDA is starting to recognize that there is now a large consortium that's been developed to try to develop intermediate endpoints to regulatory approval earlier in the disease setting, plus again particularly recognizing the importance of roughly untreated patient earlier on the whole set by giving the immune therapy earlier you should ultimately alter the course of disease. One area that I am personally very interested is the amount of PSA recurrence where we know that patients are ultimately going to develop disease and really want to know how relative non-toxic approaches to treatment that potentially can avoid giving prolonged courses of antigen drug deprivation therapy.
We've actually been able to redevelop a trial through the cooperative group looking at another platform that is actually a base platform where we were able to give this sort of take this type of report into the national cooperative group where we are giving a new therapy only in the course of PSA recurrence and where we are able to demonstrate in this was published earlier this year, is that you actually can delay time delay sort of the rate of rise of PSA so that again just sort of using the type of product where you can also delay sort of show what the rate of rise of PSA was before somebody goes on study and then demonstrate that the PSA rise goes down dramatically if you give your intervention and you can show that the slope decreases.
Now again this is sort of proof of principle not until the regulatory endpoint but again shows that immune therapy can impact only one disease and what this has allowed us to do is sort of think of -- and this was already this trial was conceived about roughly in 2005 and I think that we've learnt a lot more about how we view these type of trials in the contemporary era. One important consideration is can antigen deprivation therapy combined with immune therapy can be used some of the our known existing types of primitive prostate cancer and then combine them with a vaccine this is preclinical work [indiscernible] showing that the drug enzalutamide which essentially creates a testosterone deplete and why it's sort of testosterone just prevents the body from seeing it and that enzalutamide in fact with the vaccine in a mouse not a prostate cancer dramatically improves overall survival and that enzalutamide an antigen deprivation therapy in general, actually winds up being as a stimulus for the immune system again so just there can be no potential synergy in this regard and this is some classic drug demonstrating that androgen deprivation therapy stimulates T-Cells in humans and in fact so you give androgen deprivation therapy and then you take out somebody's prostate you can see there has been an infiltration of T-Cells into the prostate again suggesting the potential for synergy and enzalutamide has been shown to improve the overall quality of the T-Cells and the number of naive to T-Cells and improves T-Cell production.
So one sort of type of trial that we are looking forward to developing in with the Advaxis well, actually looking this early disease setting and we randomize patients to just receiving antigen deprivation therapy alone or to the combination of the ADXS-PSA plus antigen deprivation therapy. What this type of design does, it essentially resets everybody’s PSA down to zero. And then you can sort of at that point one can say if there are difference between these two arms in terms of the number of patients that ultimately develop PSA recurrence hoping that patient in this arm may never reach this threshold but PSA recurrence. And hopefully that you can file this patient at the metastases and see if there is a difference in development of metastases which the FDA has now said it is an endpoint, that they are very interested essentially, they could potentially report as a regulatory end play.
So I think there is potential to moving this platform into early disease and really impacting not just on the duration of life span towards the end of somebody’s course, but really augmenting towards a therapy that the early part of treatment. And then as you heard there is obviously great interest in combing and research in pre-clinical work in combining ADXS-PSA with radiation therapy. We know that radiation by itself actually can stimulate the immune system. And so another important area in prostate cancer that we’re very interest in, this is salvage radiation. Well, we know that prostate has to be and can -- and many men can be treated but unfortunately not in everybody. And to some extent it is a little bit naive to think that in prostate cancer that surgery by itself is going to do everything. Unfortunately know that in other tumours versus breast cancer and many other settings that often people are true multi-modality treatment through local surgery combined with radiation to sort of address the larger environment around the cancer itself.
And so this is a trial that we’re doing looking at combining we’ve at this platform with radiation that would be given for men with evidence of very-very early recurrence right after past effectively. Again, we know that salvage radiation by itself can be effective for approximately 50% of these men. And the question is can we do better than that not just by only addressing the area where the tumor used to be, where the prostate used to be, but by combining that with immune therapy that might address other type of metastatic cells that are in circulation. So really with this type of an approach with sort of hopefully a highly active immune therapy directed towards an important antigen prostate cancer. We are different looking forward to developing it in late-stage disease and ultimately moving it back earlier in the disease trajectory, and so happy to take additional questions.
Unidentified Company Representative
Do we have a question?
When you thought about the dose, pre-doses and vaccine cohorts was there a difference in activity between the first dose and the third dose?
Unidentified Company Representative
Good. At this point, I would say. There are some patients without evidence of really rapid progression in all these different dose levels. But the numbers are really quite small. So the answer is no, it’s not clear yet.
Did you measure PSA over the course of the remarks and did you get any kind of a PSA response?
Unidentified Company Representative
Stabilization, in my own patients there was, I would say again this sort of flattening of the curve being typically seen we did not see PSA declines in these initial patients.
Unidentified Company Representative
Thank you. Is there anyone else any other questions? Sure. Dr. [indiscernible], please.
Two questions, it is on us in that same trial. Did you not allow for any tolerated radiation therapy?
Unidentified Company Representative
In the initial, I don’t want to miss-speak I’m pretty sure that it was not. I am sure that was not a full effective of the plan.
And I just asked that, because you can see that radiation component. That’s of the clarity of your actual signal, because it might have a similar response.
Unidentified Company Representative
Right but there are for instance again also when [indiscernible] can [indiscernible] further, I know certainly a great interest in using systemic radiation therapies and even radio of 223 in combination with different immune platforms. There are some instances looking at giving the single simple factor sort of high dose radiation therapy to…
You are coming to my second question.
Unidentified Company Representative
Yes. Okay, please.
So on this trial, so that was my other question. Are you discussing whether to get sort of the long course radiation, which were men with prostate cancer upfront like eight weeks in this for sort of after [indiscernible] is more towards 6.5 to 7 weeks or sort of five day agro fractionated radio surgery, which we think again in some of the early data in combination with [EPI] known as PD-1 checkpoint inhibitor gives you a better [indiscernible] above for a synergistic result.
Unidentified Company Representative
That's a fascinating question that we should discuss further.
Unidentified Company Representative
No, no, in general in the salvage radiation no, because in general and not to get you [indiscernible] in the salvage radiation therapy typically exactly has been to sort of systems have reports as the result is moving more towards earlier therapies and necessarily think it's penetrated the salvage base but it's something that we're discussing.
And you may have to do your own sort of tolerability profile and that after [indiscernible] I don't think we have a lot of data for that in radiation?
Unidentified Company Representative
It is an -- thank you, that's how great ideas get formed.
Unidentified Company Representative
Any other questions? Okay well, thank you to those who joined today on the webcast and for those that are here in New York City live with us, we now ask you to join us right behind us, we've set up a reception where we can have further Q&A and informal discussion. Thank you again.