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Slide #1
SANDRA HORNING, MD: Moving on to the next segment of the program, Making the Best Treatment Decisions, Part 3, and now we're to the new therapies on the research horizon. We're going to change the order of speakers slightly for the interest of travel plans. So our first talk will be on antisense therapy. It will be given by Dr. Julie Vose who is the Professor of Medicine, Hematology/Oncology and Bone Marrow Transplantation at the University of Nebraska, where I believe she also serves as Deputy Director of the Cancer Center. Julie is a very experienced clinician, clinical researcher and author and we're happy to have her here. [APPLAUSE]
JULIE VOSE, MD: Thank you very much, Sandra. It's always a great opportunity to come and to talk to everyone and hopefully today you're going to learn something about a very new drug. This hasn't been around very long so I think there is going to be some new information today in this talk.
The drug that we're going to talk about today is called BCL-2 antisense oligonucleotide. And that's a very long, big mouthful, but I'm going to go through a couple of pieces of information you need to know about what the target is for the drug and what the drug actually does and how we'd like to use that in patients with lymphoma. And then go over what the clinical trials that have been performed have consisted of -- although there have only been a couple of trials. And then to go over with you what the current clinical trials are that are ongoing.
Slide #2
So first to understand this drug, we need to understand what we're actually trying to target with this drug. And what we're trying to target with this drug is actually the BCL-2 protein.
And BCL-2 is a family member of a series of different genes that is identified at a specific chromosome on the 1418 bearing B cell lymphomas. This is very important because this is the majority of follicular lymphomas have this particular gene, as well as about 30% of diffuse large cell lymphomas and then also CLL and a lot of other malignancies as you'll see in a minute.
This particular gen 02:46
This BCL-2 gene and its subsequent protein is expressed -- overexpressed in many type of different cancer and for our purposes today we're looking at CLL and non-Hodgkin's lymphoma. But you can see that it's also overexpressed and therefore has potential to be used in many different types of malignancies including other types of solid tumors such as breast cancer, melanoma, acute leukemia and myeloma as well.
Slide #4
This BCL-2 has been looked at rather extensively, not only in animal model systems, but also in human lymphomas and found that particular lymphomas that overexpress this BCL-2 protein do much poorly and have a much higher problem with resistance to chemotherapy. This Slide # just demonstrates -- and this particular one happens to be mouse lymphomas, but this is also true for human lymphomas -- that different types of lymphomas when treated with cyclophosphamide or in this case, a different drug. This is the survival -- tumor-free survival of the mice in this case -- or it could be obviously humans. But when their particular lymphoma overexpresses this protein, the mice have much less in the way of survival. So in this case, they're all dead by 20 days after being infected with lymphoma cell line.
This has also been shown in humans to be the case, that lymphomas that overexpress BCL-2, that they have a worse outcome than patients who do not overexpress BCL-2 protein.
Slide #5
The antisense oligonucleotide then is a very new and different type of a treatment and it's different than any other class of drugs that you've been learning about. It's a chemically modified single-strand DNA molecule, so it's actually a DNA molecule, not a protein, not a chemical. And it has a particular sequence that we're trying to do that is complementary or a mirror-image of our target RNA in the cell which is the BCL-2. It's capable of inhibiting expression of the target gene or in this case, BCL-2.
You can also have this same class of compound that can target other types of oncogenes and there are other molecules that are being studied to target these other oncogenes as well.
Slide #6
Just for your total pleasure this is the chemical outline of this particular drug so you can memorize that.
Slide # 7
Well, how does this work? The antisense oligonucleotide activity -- what we're trying to do is to take this single-stranded DNA and this is the antisense oligonucleotide, in this case, BCL-2. And we're trying to hybridize that with the RNA inside the cell. This is -- we're saying this is a lymphoma cell in this case. And we're trying to prevent the cell from doing its normal pattern which would be to translate the RNA and make BCL-2 protein. So in this case, we're trying to couple with this RNA inside the lymphoma cell and prevent the cell from being able to make this particular protein. We don't want this protein to build up because that's going to prevent the cell from dying.
Slide #8
So this is just another way to look at it and our traditional drug, chemotherapy that we've used in the past, targets the lymphoma more from this standpoint. We're trying to target it after the protein has already been made in the cell and trying to kill the cell in a non-specific way.
This particular agent is trying to actually have a mirror-image of the RNA and to prevent any translation so that the cells don't even make this protein. So it's basically a way to stop this from being made at a much earlier stage.
Slide #9
The final common pathway then for all of our agents that try to treat lymphoma is basically by this pathway. Chemotherapy in this case causes a death signal and by the mechanisms we talked about is going to cause this cell death. Again, it's not specific for the lymphoma though, it can cause any cells that are rapidly proliferating to die in this manner and that produces many of the side effects that we see.
Slide #10
BCL-2 -- this is the protein that we're trying to target, in this case, in a lymphoma cell. If BCL-2 is present and overexpressed it prevents this pathway from going on and prevents cell death. So that these tumor cells then can survive immortally.
Slide #11
The antisense oligonucleotide, then we're trying to target this particular protein, BCL-2 and to allow this pathway to go on and to produce cell death of the lymphoma.
Slide #12
This has been shown in animal model systems and this is just a way to show you that this drug probably is going to work best in combination with chemotherapy, although it has been used and has some anti-lymphoma effects when used alone. This particular model is a lymphoma model in mice and this is the use of Cytoxan or cyclophosphamide to kill the lymphoma. And what they found that the survival of the mice was only about 35%.
The Genasense or in this case the BCL-2 antisense oligonucleotide was survival of 60 days. If you added the two together, the mice survived quite a bit longer. And therefore, it is felt that these two together would be synergistic or more than just additive to try and improve the results of patients with lymphoma.
Slide #13
It's also been found that this Genasense or anti-BCL-2 oligonucleotide is very specific in that it appears to target the cells that overexpress BCL-2, but does not actually target the cells that do not overexpress BCL-2. So what this shows is the specific activity of BCL-2 in these cells that are BCL-2 positive with the Genasense and does not affect those that are negative.
Slide #14
This has also been shown to be additive in CLL cells. The two I just showed you were actually non-Hodgkin's lymphoma mouse models. And this is CLL cells that shows that the two appear to be additive with, in this case, fludarabine and dexamethasone.
Slide #15
There has also been some very nice work done trying to look at the addition of antisense BCL-2 to other agents such as rituximab and hopefully in the future other monoclonal antibodies as well. And this again is showing that the addition in green here, this is the apoptosis analysis -- that's the programmed cell death that we talked about -- that we want to try and make sure that we're having. With rituximab you can see it at various different doses in the green here. And if you add the BCL-2 antisense oligonucleotide to rituximab at the same dose you can see increased apoptosis or programmed cell death at the various increasing doses. And therefore it's felt that the addition of these two together may also be another good way to go as far as therapy.
Slide #16
What are the clinical trials that have been performed with this particular molecule and what are the ones that are currently ongoing?
The first clinical trial that was performed with this was done in England at the Royal Marsden. And they did a 14-day subcutaneous infusion of this Genasense antisense oligonucleotide. It was a dose-escalation, phase I study. So that means that they started at a lower dose and increased the dose as they treated more patients to be sure that it was safe. And they went up to a maximum tolerated dose -- that was quite a high dose. This appeared to be quite well tolerated. The dose-limiting toxicity or side effect that they felt they saw with this particular drug was first thrombocytopenia or low platelet count (and that's something that we see with many of our different chemotherapy drugs as well), flu-like symptoms, fevers, and malaise or tiredness and at the very highest doses, low blood pressure.
Slide #17
What they found in their very small initial study -- one patient had a complete response. And that is, that when they reevaluated the patient, all of their lymphoma was gone as best as we can tell based on CAT scan, bone marrow biopsies, etc. And that patient was a follicular lymphoma patient and actually has stayed in remission now past three years.
There are also some minor responses, stable disease in some patients. Some patients they felt had improvement of B symptoms or the fevers and night sweats and weight loss that some patients have. They also evaluated the circulating lymphoma cells in the blood and felt that 10 out of 14 patients had reduction or disappearance of lymphoma cells in the blood based on this therapy. And another thing that we look at is the reduced LDH or lactic dehydrogenase. It's a blood test to look at the activity of the lymphoma. And they felt that four patients had that go down with the treatment.
Slide # 18
So this is a very early treatment, but I think a very important look at this, but it does have some activity when used alone. And we think that most of this activity will be used in combination.
This is just a cat-scan to show the patient that did have an excellent response to this. It can be a little hard to see, but this is a cat-scan of the chest. And this is lymph nodes in the axillary area or under the armpit that the patient had prior to treatment. At 18 months after the treatment, this is the cat-scan showing that all those lymph nodes are gone. And you'll just have to take my word on it that the rest of the lymph nodes in the body also were of abnormal size. And that patient continues to be in remission three years, past three years.
Slide # 19
There has also been some very early trials looking at this particular agent in chronic lymphocytic leukemia or CLL or the counterpart of that would be small lymphocytic lymphoma in patients. This has been a dose escalation trial and they tried to go up a little bit higher on the dose. What they found was that there were some patients that at very high doses had what's called "tumor lysis" syndrome. And that's a good and a bad thing. That means that the treatment itself actually lysed much of the lymphoma cells, the leukemia cells very rapidly and that the patient had some symptoms related to too much of the cells being treated with this. They had one patient that experienced that and then they went down on the dose.
They did find that several patients had decrease in lymph node size, decrease in spleen size in one patient, and decrease in the lymphoma count -- lymphocytes in the blood in several patients -- about 33% of the patients. So it was felt based on just single-agent activity that it did have an effectiveness in both CLL and non-Hodgkin's lymphoma.
Slide #20
This is just an example of some information that Susan O'Brien from MD Anderson reported based on the CLL trial. In that the patient here was treated with the Genasense. This is given by a continuous infusion, through a pump, and typically it's given for seven days now in most of the clinical trials. And during that time period, the patients white count fell dramatically from 120,000 down to close to normal and still above 20,000. And as soon as the infusion was stopped, the white count did go back up.
So this is more of a treatment that is going to need to be given on an ongoing or intermittent basis as we do with other cycles of therapy as well.
Slide #21
So what are the current trials that are going on in the United States? And there are several that I list that I'd just like to point out to you today.
The one that's the furthest along is in the chronic lymphocytic leukemia trial. This is actually a phase III trial which means that it's well on its way to being presented to the FDA for possible approval when this trial is completed as one of their applications.
This trial is for patients with chronic lymphocytic leukemia who have had prior fludarabine which is a very common drug that's given to patients with CLL. No prior stem cell transplantation. And these patients then are randomized to receive either fludarabine-Cytoxan, which is a treatment that has been found to be effective in patients who failed prior fludarabine, or they're randomized to received fludarabine, Cytoxan and the Genasense antisense BCL-2 oligonucleotide. And this is a current study that is ongoing.
Slide #22
As I mentioned before, there are many different trials, however, not just in lymphoma. And this is just a Slide # to show you that this is also being tested in many other diseases such as lung cancer, leukemia, multiple myeloma, prostate cancer, and a host of other malignancies that this is going to be tested against because it's not going to be necessarily specific just to lymphoma.
Slide #23
So just to finish up, these are the current clinical trials that are going on that I am aware of with this particular agent. And I was going to go through those with you. The one I talked about CLL which is the fludarabine-Cytoxan vs. fludarabine-Cytoxan and Genasense. And this is a multicenter trial. It's available at many centers throughout the United States. You can ask your oncologist about that, if you're interested.
The rest of these are smaller phase I and phase II trials that are just the first trials that are being done in different types of lymphomas.
Diffuse large B cell lymphoma. There is a trial that's going on with CHOP-rituxan, plus the Genasense, at several different centers -- Stanford, Vancouver and Nashville.
For patients with recurrent lymphoma, follicular lymphoma -- there is a trial that's going on with the addition of rituxan plus Genasense based on the information I showed you previously that the two together appear to act very synergistically. And this is at MD Anderson, in Philadelphia and Toronto.
There is a mantle cell lymphoma trial that for patients with recurrent mantle cell lymphoma, that have previously received CHOP. They can receive the Genasense alone as an infusion for several cycles. And then, if they fail that, they can go on to receive CHOP plus rituxan if they have not previously received it.
For patients that are newly diagnosed, then they can also go on this study to receive Genasense alone, and then to go on to CHOP plus rituxan plus the Genasense to see if that combination is synergistic. And this particular trial is going on at our place, University of Nebraska, in New York, Los Angeles, Nashville, Atlanta and Rochester, New York.
And the last trial is one in post-transplant lymphoproliferative disease and that's the addition of rituxan to Genasense, again based on the information I showed you previously that the two together appear to be quite active.
If you have questions regarding these or other clinical trials, I just put the number on here that you can call. It's 1-888-864-3682. And you can certainly e-mail or call me and I'd be happy to help you with any questions about that as well. Thank you very much.
And I'm going to take a few question now because I am going to have to leave unfortunately. [APPLAUSE]
Q: Could you clarify the difference between being BCL-2 negative and PCR negative? I'm still confused about that.
JULIE VOSE, MD: PCR is just the name of a test that we do to detect the BCL-2. So that's more of a technical test. The BCL-2 is actually the protein that we're trying to test with the PCR. Does that answer your question?
Q: You may have answered my question. Then what I wanted to know is how can you tell if you're cells are expressing too much the BCL-2?
JULIE VOSE, MD: Right. That is a test that has to be done in the laboratory on the lymphoma or on the cells from the blood or bone marrow. And that can be done with some special stains and tests, either by actually slicing up the lymphoma and doing some stains on that or by doing what's called "flow cytometry" or by doing this PCR test. So there are a number of different ways to do that to find out if the lymphoma or cells are having this BCL-2 expression and to look at what the extent of it is.
Q: And where do you have that done?
JULIE VOSE, MD: That's something that is done in a pathology laboratory so that would be something that your oncologist would need to request.
Q: Thank you.
JULIE VOSE, MD: Any other questions I can answer for anyone? Okay. Thank you very much.
[APPLAUSE]
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