Topic: The focus of the interview will be their new Phase 3 gene therapy clinical trial evaluating the efficacy and safety of intrapleural administration of adenovirus-delivered interferon Alpha-2b (rAd-IFN) in combination with celecoxib and gemcitabine in patients with malignant pleural mesothelioma.
About the Speakers:
Dr. Albelda is a pulmonologist at the University of Pennsylvania. His research goal is to develop novel approaches to the treatment of lung cancer and mesothelioma, with special emphasis on gene and immunotherapy.
Dr. Sterman is a pulmonologist at NYU. Over the past 22 years, he has focused on the translation of laboratory discoveries from the bench to the bedside: conducting multiple Phase I human clinical trials of gene therapy and vaccine therapy for lung cancer, mesothelioma, and other pleural malignancies. Dr. Sterman’s current interests include immunophenotyping of lymph nodes in thoracic malignancies, and development of novel intranodal, intratumoral, and intrapleural therapies as adjuncts to systemic checkpoint inhibition in lung cancer and mesothelioma.
This live broadcast is made possible by an educational grant by Trizell Ltd.
Full Transcription:
Mary Hesdorffer (MH): Thank you, Drs. Albelda and Sterman, for taking part in this special podcast. I think it is a great opportunity to see a Phase 3 study be available to mesothelioma patients. It is a complicated trial, so I think it would be very important to start with some background, and how we got to a Phase 3 using these agents. The two of you have worked for many, many years in this field and are pioneers in gene therapy. Dr. Albelda, would you like to start with a little bit of an introduction to this?
Dr. Steve Albelda (SA): This trial had its roots more than 20 years ago when we were first developing ideas for gene therapy: that is, to use viruses to put in specific genes into the tumor cell it might make it more sensitive to killing or directly activating the immune system.
We’ve done a lot of work in the laboratory where we have models of mesothelioma that were actually caused by asbestos but that grow in mice and we injected these viruses – these viruses are not toxic. They are not able to replicate by themselves so they’re very safe. We injected those into the pleural or peritoneal cavity of the mice, and we’ve been able to show that these viruses can activate the immune system and by themselves cause the tumors to go away, or in combination with other drugs, they work even better. Based on these laboratory studies, we started a series of Phase 1 clinical trials, these are trials that are very early, that are mostly focused on safety and give us some idea of the efficacy (how well the virus actually works).
Dr. Sterman ran those initial trials that led up to this trial.
MH: So, Dr. Albelda, you basically spent your time in the lab and Dr. Sterman is the one who has the face with the patients and does the humanized clinical trials, correct?
SA: Exactly. We help on the other end, when we get samples from the patients we analyze those to give us an idea why things didn’t work or did work, we try to improve it in the laboratory then give the new and improved version to Dr. Sterman to try in the next clinical trial. It’s an iterative process. Start first with a simplest idea—see how that works—then build on it and build on it. And that’s where we are today, after 20 years, this final trial, which is a little more complicated, involves the gene therapy with chemotherapy together.
MH: Thank you. Dr. Sterman, would you like to speak a little bit about some of the early iteration of the clinical trials that led up to today?
Dr. Daniel Sterman (DS): Certainly. The earliest clinical trials that we did were well over 20 years ago, and they really proved the principle that you could deliver genes into the chest cavity of patients with mesothelioma and get those genes into the tumor cells to express the gene of interest in the tumor cell and actually demonstrate some clinical responses.
Those early clinical responses we saw from the gene therapy clinical trials in the late 1990s really gave us the clue that what we needed to be doing was to focus on activating the immune system. And so, the genes that we were focusing on after 2003 were genes that were part of, what’s called the interferon system, which is a system that we all have in our bodies to help us fight infections, but interferons have been used in cancer treatment, and specifically in mesothelioma treatment for many years, but with minimal success – in part because it’s not a very efficient way to deliver the interferon itself to the patient with cancer. The interferon itself can cause a lot of toxicity and dose required is very high. And so we were studying in patients whether or not we could use this modified cold virus to deliver the gene for interferon rather than interferon itself. So the virus would be injected into the patient’s chest cavity, the gene that encodes for the interferon would get into the tumor cell, the tumor cell would become a factory to produce interferon within the tumor itself, and then this would activate a variety of immune responses in the tumor and in the chest cavity that would then go systemically. And our first trial that we conducted and published well over a decade ago in this area, where we gave one or two doses of this cold virus expressing the interferon into the chest cavities of patients with mesothelioma who had been through many different treatments beforehand. So they had been through chemotherapy, and surgery and radiation, and combinations thereof, and were well enough to get into our study but had exhausted standard forms of treatment. It was remarkable about this first in human trial that 4 of these 9 patients that we initially treated (we treated a total of 11 in that first trial) but 4 of the first 9 had evidence of response on CT scan and PET scan that we were not expecting. It was a trial primarily to prove safety and feasibility, and we weren’t looking for responses. That was really remarkable and one of those patients had a response which was nearly a complete response over a period of about six months with no other treatment during that time. It was really astounding and told us what we were doing by injecting this virus locally into the chest cavity was really creating a systemic immune response and activating the body’s own immune defenses against the mesothelioma wherever it might be and at a far distance from where we had done the injection.
This was incredibly exciting to us, and what we wanted to know next was if we then combined this approach with standard treatments for mesothelioma – chemotherapy for example – could we see any improvements compared to say chemotherapy alone or the virus alone. So the next trial we did was looking at combinations of the cold virus delivered interferon gene, with chemotherapy, and we added a third compound, which is a drug called Celebrex, which is an arthritis drug approved by the FDA in routine use for people with arthritis and other joint complaints, but it has a unique property in that it actually prepares the mesothelioma tumor for a better response to immune stimulation treatments like our immune gene therapy with interferon. It does this essentially by reconditioning the environment of the tumor so that it’s less immunosuppressive. So, this combination of the oral Celebrex, the arthritis drug, the dosing of the cold virus expressive of the interferon gene into the chest cavity, and chemotherapy showed in a subset of patients a significant improvement in overall survival compared to what’s been published before with chemotherapy alone. And this subset were those patients who had been through front-line treatment and had failed front-line treatment and were now getting their second line of chemotherapy. This was really exciting that typical survival rates for patients who are getting second-line chemotherapy in mesothelioma are only about 6 to 9 months and our average survival of all these patients was about double that around 17 months. This was incredibly exciting to us and was the impetus for the development of this current trial.
MH: There is a lot of background, and there is a lot of knowledge about drugs, about toxicities, and what to expect. Let’s move now into this trial. Now we have a Phase 3 trial – can you talk a bit about the schema of the trial and what it looks like for the patients?
DS: It is a complicated trial, but from a patient’s perspective, it is relatively straight forward. The patients who are eligible for our study are patients who at some point in the course of their treatment have received a treatment with chemotherapy, which is based upon the mainstay drug of chemotherapy, pemetrexed also known as Alimta, and if they’ve received a combination chemotherapy with pemetrexed or Alimta in it, and ultimately have progressed, then they are potentially a candidate for this study.
It’s for patients who had chemotherapy. Now, the chemotherapy could have been before or after surgical resection and have had recurrence at that point, or potentially they could have received radiation therapy and chemotherapy for their mesothelioma and now have evidence of disease progression. Patients also are allowed to have a second course of therapy before entering this study, which means that this study is for patients in what’s called the second or third line and that second course of therapy could be a different immunotherapy including some of the drugs that are being studied in mesothelioma currently. So, having been in an immunotherapy trial before and then demonstrating disease progression does not exclude the patient from being enrolled in the study. We’re only enrolling patients with a certain cellular type of mesothelioma, the epithelioid and an epithelioid-predominant form, because those are the patients that seemed to respond best in the earlier combination study that we did. Patients when they have had their entry criteria evaluated by their oncologist and referred into a center enrolling patients in this study, they will then be randomized, which means they’ll have a 50-50 chance of going into one of two groups. One group will receive the injection through a small catheter into the chest cavity of a single dose of the cold virus containing the interferon gene in combination with Celebrex orally for two weeks, and then they’ll get a standard form of second-line or third-line chemotherapy called gemcitabine, which will be given on a standard treatment regimen and schedule. The other group of patients who don’t get randomized into getting the gene therapy will get the Celebrex and then will get the standard gemcitabine. And then we follow the patients for as long as they are continued in the study, and they’ll also continue on gemcitabine chemotherapy until they have evidence that the disease is progressing. And what we’re looking at is which group of patients live longer, and we’re hoping that the triple combination of therapy which includes the gene therapy patients will demonstrate what we saw in the earlier trials which a significant improvement in survival for the patients.
MH: If patients are interested in this study, first they would make an appointment with yourself or one of the other centers that are conducting the trial under your direction. They would come, you would explain the trial to them, you would do a consent, you would do some standardized testing, then they would come back to you to begin the study?
DS: That’s correct.
MH: So, they would expect them to be at any given center maybe a day or two for the initiation and then they would come back to start. Let’s just say they’re coming to you in New York, Dr. Sterman – how long would they be expected to be in New York for?
DS: Initially, they would be in New York for several days. If they’re randomized for the infusion, we would then arrange for a catheter to be placed into their chest cavity. This catheter can be placed through a number of means. If there’s enough fluid, myself or one of my colleagues in the interventional pulmonary team can place the catheter under local anesthesia, and a little bit of sedation. Alternatively, if there is a small pocket of fluid that needs to be accessed through image guidance, we would have the interventional radiologist place a small [thin-tailed] catheter into that space. And in some occasions, we might ask our thoracic surgery colleagues – at NYU that would be Dr. Harvey Pass, one of the world’s experts in mesothelioma treatment – to help us in placing the catheter surgically. We would then instill the dose of the virus through the catheter on the following day – allowing about 24 hours for the catheter site to heal – and then once the virus has been instilled into that space in the chest, and the catheter is no longer needed clinically, we would then remove the catheter. The patients would then take the Celebrex pills, which would be given to them by our research staff, and those pills are taken orally so they can be taken at home. So, they would be at our center in New York or other centers around the country or the world for a relatively short period of time to make sure there were no short-term side effects from getting the injection into the chest cavity. But the Celebrex is given over a two-week period without any need to be physically present in the site where the study is being conducted. And then afterwards they would return to our center, or the other centers conducting the study, to initiate the chemotherapy portion of the protocol. If the patients are randomized to the Celebrex and chemotherapy alone, then there would be no need for a catheter to be placed, there would be no injection through the catheter, and they would just be given the pills of the Celebrex to take at home and would follow up at our site for initiation of the chemotherapy as they would in standard of care.
MH: And the chemotherapy then would then be given every two weeks?
DS: It’s a 21-day cycle where they get it on day 1 and day 8 of the 21 days.
MH: So, they’d have to come back and forth two weeks in a row for one day to get the infusion?
DS: That’s right. It’s an outpatient visit, very-well tolerated, routine standard chemotherapy that we’d be administering.
MH: I know that gemcitabine is given as a standard second-line treatment, so I think one of the important things that you and I have discussed is getting the word to patients. If you’re a patient who hasn’t started treatment or you’re a patient who is now looking about for this next line of therapy, before you accept gemcitabine, it would be very important to discuss with your doctor that there is this trial taking place, and if you have gemcitabine, it would make you ineligible for the trial. I think these discussions need to take place. First of all, are you interested in a clinical trial? And if you are, the need to sit down with an expert and talk about the clinical trials that you might eligible for and get some guidance on how to line them up. This way you would get maximum exposure, and you don’t knock a trial out of your line-up by having one trial where you should have another trial first. I think these are discussions we need to have in all the clinics when we have these types of trials. Especially with a trial that’s going to utilize gemcitabine, which is so commonly given in the community and academic centers. We really need to make everyone cognizant that we have this trial – a Phase 3 trial, meaning that there is good data and good knowledge about the drug that we really want to make sure that this is prioritized and really looked at as a serious contender in the clinical trials arena.
SA: If a patient gets the infusion and then they have to get gemcitabine, can they get the gemcitabine at their local hospital, or do they have to get it at one of the study centers?
DS: As of right now, the protocol states that they have to get it at the study center. We do, however, have centers all across the United States and more and more centers are coming online. So, my hope is that patients don’t have to travel so far. I can’t guarantee anything, but it’s possible we might make modifications that if the patient is doing really well on the study, and tolerating the gemcitabine very well, there don’t seem to be any side effects, they seem to be having a response, we may be able to in certain circumstances get amendments to the protocol that allow the administration of the drug closer to home. That being said, right now the protocol says they need to be getting chemotherapy at their study center.
MH: Dr. Sterman, you have a lot of experience giving all of these drugs. Can you talk a bit about the side effect profile that you’ve observed to date?
DS: Sure. One of the major side effects of giving this cold virus into the chest cavity, which carries the interferon gene, is a response called cytokine release syndrome. And it’s a pretty mild cytokine release syndrome and what this refers to is that when the virus, even though it’s modified and can’t reproduce itself inside the patient, is injected, it can cause fever, chills, slightly low blood pressure. The nice thing about the way the study is designed is we’ve shown in our clinical trials that we’ve done before that the Celebrex modified the tumor so that it’s more effective in its response to interferon gene therapy. The Celebrex also mitigates (decreases) the fever and the chills and the other side effects.
In our most recent trial, when we added the Celebrex, those side effects were really minimal and very well tolerated. Fever and chills generally last for about 24 hours, sometimes 36 hours after the gene therapy virus is instilled into the chest cavity. And in some patients, primarily in those who had the catheter placed by a surgical procedure, they would have symptoms that we ascribe to the production of the interferon within the tumor within the chest cavity. And this would be a lower grade fever, maybe some mild nausea, maybe some mild muscle aches. And these are symptoms that are very characteristic of interferon treatment that is part of the standard medical treatment for a variety of disorders, including some cancers. And this lasts for a couple of weeks but is generally very well tolerated, and primarily seen in those patients who had their catheters inserted surgically. In those patients who don’t have the gene injected into their chest cavity and are just getting the Celebrex and the gemcitabine, the Celebrex is exceedingly well tolerated. It’s helpful with pain control in those patients who are having chest wall pain in connection with their mesothelioma. And the side effects of gemcitabine are fairly well studied, and at this point the issues with side effects of chemotherapy have been dealt with a lot of the medications we use to pre-medicate patients to prevent them from having the typical nausea and vomiting and other side effects related to chemotherapy.
MH: It does sound like it’s a fairly well-tolerated regimen. Right now, I believe the study is open at NYU, I believe in Tennessee?
DS: We have sites that are open at the University of Maryland, sites open at the University of Kansas, a site open at UCLA, and we are enrolling our first patient in the world in Glasgow in Scotland shortly. That patient will be dosed on the 17th of September.
MH: Most of the centers you mentioned have arrangements with various hotels to get a discounted rate for patients. In New York, you also have that opportunity of the Hope Lodge. So there are opportunities to help patients who come in for these treatments who have to travel. And as you know we have our travel grant program where we are committed to getting patients to an expert, and if patients enroll in a clinical trial, we are there also to help them with the back and forth travel. I think that though there is always an out-of-pocket expense, I think there are ways of mitigating the expenses that take place with some of these clinical trials.
Dr. Sterman, I have a few questions from the peritoneal patients. If they have metastatic disease into the chest, so they now have disease in the pleural cavity, would they be eligible for this trial?
DS: Not currently as the trial is designed. This creates an interesting question because there is no reason why the gene therapy treatment that Dr. Albelda developed in his laboratory wouldn’t work for those patients. In some of our previous trials we did enroll patients with pleural extension of peritoneal mesothelioma into our studies and they seemed to be very well tolerated. I don’t think we have enough numbers to know whether their responses were significant or not. But I do think it begs the question of a separate study in peritoneal mesothelioma down the road. This trial is limited to patients with pleural mesothelioma, and I realize this is challenge because the peritoneal mesothelioma community is relatively small compared to the pleural mesothelioma community and really needs good Phase 3 clinical trials to study new novel therapies. Unfortunately, for trying to make our study as uniform as possible, we had to exclude some subsets of mesothelioma patients, including those with peritoneal involvement, pericardial involvement, involvement of the scrotum. So, this is a pleural-only study, unfortunately.
MH: Okay, looking at prior regimens, are you counting intrapleural chemotherapy, the heated chemo into the chest. Does that count as a regimen?
DS: I think we’d have to take it up with the medical monitor of the study, but it’s an excellent question that we’ll have to address. I’m not sure I have the answer to that right now.
MH: I’ve had some interest from people who are looking ahead, who have had intrapleural and are counting the number of treatments that they’ve had. So, another thing we should point out that’s different in this trial. When we talk about gene therapy trials, about some of the targeted trials and some of the mutations, the word “gene” automatically comes up with “mutation.” You’re not looking for a mutated gene in this trial, you’re looking for all comers who have predominantly epithelioid mesothelioma so having had mutation analysis is not necessary for this trial. Am I correct?
DS: You are, and I’ll let Dr. Albelda expound on that.
SA: There is no genetic requirement for this trial. If a patient has a BAP-1 mutation, it really doesn’t make a difference. One other question that Dr. Sterman might discuss a little bit is, which he really didn’t talk about, is one of the requirements for the trial is that you have to have some fluid in the chest to allow us to put that catheter in, so Dr. Sterman, could you talk about that a little bit?
DS: Sure. Let me clarify, because I think this is a little bit of a misunderstanding, you have to have what we describe as “an accessible pleural space.” An accessible pleural space can be anything from a patient having a large amount of fluid that can be easily drained with a needle, tube or a catheter, or a small amount of fluid that could be accessed by a radiologist putting a small pigtail [catheter] in, or even minimal fluid but a chest cavity that a surgeon can access with a minimally invasive procedure.
What’s important to understand is that if patients otherwise met all entry criteria and have a very, very small amount of fluid, they are still not necessarily excluded from the study as long as we can find a way to safely and easily get a catheter in. And the catheter does not have to have access to the entire pleural space. One of the real remarkable things we showed in our earlier studies was that some of our most dramatic responses were injecting the virus into a very small cavity, a very small space, one in which there was not a free-flowing fluid throughout the entire chest cavity. It’s really important to understand that there are a variety of types of patients with various amounts of fluid remaining or not remaining in their chest who may still be eligible.
MH: Thank you for clarifying that. We’re now getting into flu season – so what’s the timing for flu shots prior to this trial?
DS: We have no limitations in terms of the flu vaccine and no expected interactions between the two. Although, there are so patients who will develop a mild febrile reaction to the flu shot, which could – if you got it right at the type of the clinical trial, which is probably not a good idea – we could mistake some of the side effects of the flu shot to the side effects of the treatment. Although we didn’t explicitly say it in the protocol, my guess is you should get your flu shot either well before the gene therapy installation or at least a few weeks afterward.
MH: Thank you. I guess with everyone on the phone I would encourage you to speak with your doctor soon, because flu season is approaching, vaccines are available now, and considering you’re thinking about new therapy or you’re currently on therapy, it’s important to get your physician’s input as to the timing of the vaccine and not to shy away from them because they aren’t lifesaving, particularly when you’ve been compromised. I think we have a pretty good idea of this trial. Is there anything else that either of you would like to bring up?
DS: Steve?
SA: We have had a lot of experience with this. We have treated 40 patients already, so I think we have a pretty good idea of the side effects, which have been very minimal, so I think it’s really quite a safe trial for patients.
When we started this idea of using the immune system to treat mesothelioma, it was – I wouldn’t say laughed at – but not considered so seriously. With the recent successes of the pembrolizumab treatment in a subset of patients who have had responses, it’s now very clear that mesothelioma is a disease that can be targeted by the immune system. This trial is working in a completely different way than pembrolizumab; although, we think it might be complementary to that. As Dr. Sterman mentioned, if a patient is treated with chemotherapy and then put on pembrolizumab, they would still be eligible for this trial – in fact, we think that prior pembrolizumab might even make this work better.
MH: Interesting. That’s good to know.
DS: I just want to add a comment regarding the significance of having a Phase 3 trial in mesothelioma. Now I don’t know if everyone on the call knows what the different phases of a clinical trial are and what the implications of having a Phase 3, multicenter, international study are.
So, just to remind everybody, a Phase 1 study is the earliest phase of any clinical trial, and it’s where you take a novel compound and you’re giving it to patients, and there really is no expectation of benefit for the patient, but it’s to study whether the new drug is safe and well tolerated and what the proper dosage is. Once it goes through Phase 1 trial, you go to a Phase 2 trial, where you’re taking a larger number of patients, you’re giving them a standard dose of the novel drug, and you’re looking to see what kind of responses and how many responses you’re seeing, and, again, looking for safety and toxicity. In a Phase 3 trial, you take the novel drug – in our case, it’s the interferon alpha gene therapy – and you compare it with a standard of care. In our case, that standard of care would be chemotherapy. It’s a little bit different because we’re combining the two, but really it’s looking at a novel combination versus the standard of care.
The goal is to get a definitive answer – not just a suggestion – a definitive answer as to whether the new treatment is better than the standard of care. The goal of a Phase 3 trial for patients with mesothelioma is that we hope it works out in the way the studies have shown so far that we may have a new treatment option – a routine, standard of care treatment option – to offer to patients with mesothelioma who have been through front-line chemotherapy.
In mesothelioma, the FDA has only approved two treatments in the last 16 years. It approved pemetrexed in 2003 and just a couple of months ago approved – in combination with front-line chemotherapy – a new treatment called tumor treating fields under special circumstance. So, a Phase 3 trial gives a possibility – we have no idea what the results will be – but the possibility of having another important drug in our armamentarium that would potentially have proven benefits for mesothelioma patients. For the field of mesothelioma, and led by the Meso Foundation in terms of its sponsorship for scientific research, we need to be able to develop these proven treatments so that we can provide better quality of life, better quantity of life, and, some day, a cure for patients with mesothelioma.
MH: Thank you. Dr. Sterman, I neglected to ask. How many patients do we need to accrue?
DS: We don’t know. It’s going to be approximately 300 patients, but the way it’s designed is through a novel statistical program that we look at the responses after a certain number of patients, and if we achieve a certain threshold, then there might be a lesser number of patients that we would need to accrue. But it’s going to be around 300 to 400 patients, and it’s a worldwide study, so there are multiple centers in the United States – several which are already activated – centers throughout the United Kingdom, Europe and Russia, and we’re even potentially discussing adding additional sites in Asia down the road. It’s very exciting to have such a Phase 3 worldwide clinical trial.
MH: Congratulations. Because after years of hard work and kicking down doors with gene therapy and immunotherapy, as you said, something you and Dr. Albelda were the early pioneers in the states, it’s nice to see that you’ve taken this to a Phase 3. So often we see things that are promising but then they sort of drop out, and it takes a lot of perseverance and a lot of hard work to get to a Phase 3. I think this is really exciting.
I’ll just ask, is there anyone who wants to ask any questions? Please send to Maja or post a Facebook question now before we conclude the call. I have one direct question that I just want to read it quickly.
The question I had was, why are they limiting the criteria for the Phase 3 trial to epithelioid tumors versus to biphasic that have great than 50% sarcomatoid cells? I think that you may have mentioned that you didn’t see much activity in sarcomatoid meso, am I correct?
DS: That is correct.
MH: Okay, so that’s the reason, at this point, for limiting it to mainly epithelial mesothelioma. Alright, so I think we have our matching orders. We’re going to make sure that we let as many people as possible know about this trial. Again, I want to emphasis that if you’re looking for a new line of therapy or you’re in the process of considering second line, please always be aware that if you have gemcitabine, it will render you ineligible for this trial. If gemcitabine is being discussed as a potential treatment for you, make sure your doctor is aware of this trial. You can contact the Foundation, you can contact Dr. Sterman, we are more than happy to provide any information to your physician about the trial.
Dr. Sterman and Dr. Albelda, thank you so much for your time. Congratulations, again, on this exciting study. I just think that, as you said, a Phase 3 in mesothelioma is so important, and to be able to get these drugs into the hands of patients, having also mentioned about peritoneal mesothelioma, I think that we bear in mind as well that once a new study is approved in mesothelioma, it makes it much easier to get into the hands of peritoneal mesothelioma patients as well. It’s not far behind if this trial proves itself. Phase 3 can get expedited if things go well.
Thank you, again, for participating in tonight’s call. Thank you everyone who was on the line, and, again, if you have questions that you’re still formulating or thinking about, if I can answer them, I will; if not, I’ll get to Dr. Albelda or Dr. Sterman to pose any questions that we might need answered. Good night, everyone, and thank you so very much.
