Patient Power Knowledge. Confidence. Hope. Aiming for a CLL Treatment Home Run Recorded on June 1, 2014 Thomas Kipps, MD, PhD Deputy Director of Research Operations UC San Diego Moores Cancer Center Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Dr. Brian Koffman at ASCO 2014. And, Dr. Kipps, you want to introduce yourself? Yes. My name is Dr. Tom Kipps. I'm at the UC San Diego Moores Cancer Center in San Diego, California. One of the things that I beg is not to be left on third base. I mean, I'm very grateful that I'm on the ibrutinib (Imbruvica) and that I've been able to get this deep remission lots of people have. But we were starting to talk about this, and I know this is an area that you're interested in is how do you get somebody from third to home. You know, home may be being starting with MRD negative and you're getting to cure, so if you could kind of touch on that. Well, I think it's really important. I mean, there's a determining factor, which is called minimal residual disease, which is something that you can assess usually after treatment. Now, with drugs such as ibrutinib and other kinase inhibitors, not many patients, very few it's the exception that can achieve what's called complete remission. Now the idelalisib would be in that group. Idelalisib or IPI 145 or other agents that are coming down the pike. ONO-4059. There's over 20 now that are being out there, but they are unable to close the deal and like you say get you home, maybe strand you on second or third base. Most patients achieve a partial remission, and the unfortunate thing is when you stop the medicine many patients may experience a relapse of the disease within a very short time, and so it's not a good idea to stop the medicine. However, I think that if we can achieve a perhaps deeper remission and allow you to stop taking the medicine altogether, can some of those patients who achieve that actually achieve a cure? We hope so. Now, we've been working with this compound ABT-199. It's being co-developed by AbbVie and Genentech, and we're very excited about this drug. We've been fortunate to be involved in some of the early trials, and we continue to have many trials with this drug. I'm very impressed with it. It really does target a key facet of the disease. In other words, one of the signature features of this disease is a very high level expression of a protein called BCL2.
Yeah, tell us about that. BCL2 is like putting the brake on your cell's ability to die. And so we look at the CLL cell, and it's really a cell on the razor's edge. It has this BCL2 protein, which puts a brake on cell death. But also in CLL they have a mechanism, another protein BIM, which is able to push the cell over the cliff. So it's almost like, sometimes say it's like the flying buttress of the Cathedral of Notre Dame. You have one end going here to die, one end to survive, so that's a balance. And the leukemic cell has been engineered because of the fact that it's a B cell to be on that balance. And the reason for that is that normally B cells have to go through this very tight gauntlet. And if they don't have all the right things that it takes to make a good immune response, they're really programmed to selfdestruct. Now the leukemia cells manage to figure out a way to get beyond that gauntlet and just exist and then to grow. But if you take out BCL2, it's like taking off the flying buttress of the Cathedral of Notre Dame. The whole structure starts to collapse. So it's really critical. So with the identification of these proteins, there's ways of which they have been found to fit together. It's like a lock-key relationship. So if you have these proteins, it's the yin-yang of leukemia. And if you get a small molecule that can actually interface with this, it can take away that lock and allow the protein that's going to cause cell death to do its job. And so it really is quite dramatic because when you add small molecules inhibitors of this protein BCL2 it allows for that internal machinery to take effect, and the cell can undergo cell death. And it's quite specific because CLL cells are wired this way, but the rest of our cells in the body are much more resilient. All right. So this is actually a very targeted therapy, and it's targeted to a known molecular lesion in the cell. I mean, years ago with Carlo Croce and others in the CLL research consortium, some of the genes that are found to be lost in CLL are the ones that can repress the expression of BCL2. So BCL2 expression goes higher and higher, and it gives that mechanism of escape from this gauntlet allowing the leukemic cells to survive. So what it is attacking a very basic principle of leukemia. That's critical because I think what it might do is actually affect maybe potentially eradication of the disease, potentially in some patients. And some of the data has been really exciting. Yes. We've been actually very excited. We have had patients who have failed such therapies as fludarabine (Fludara), cyclophosphine, rituximab (Rituxan) FCR. have failed alemtuzumab (Campath) and did not achieve what's called absence of minimal residual disease. These patients are actually ones that, some of them went into our trial with 199 as a single agent, and they experienced dramatic reductions in their lymph nodes and their white cell count. And when it came right down to it, we couldn't detect any enlarged lymph nodes by CT scan. We did the marrow, and under sensitive methods we could not detect leukemic cells in the marrow. Now, I advocated that we should stop therapy. There was some concern about wanting to continue therapy. But in my mind if we don't have any evidence of disease, why can't we stop the treatment? So we have actually done that in some of our patients, and they have gone on to do well. They haven't had recurrent disease. Some are out since July of last year Wow.
And so we're following those patients. But that is very exciting. So the questions that remain with this is how best to use it. As you know, it sometimes in certain patients can be reaching like a tipping point. So patients who have very large tumor burdens, if you completely allow the leukemic cells like the Cathedral of Notre Dame, you can get some collateral damage there. And there have been some deaths. There's been some deaths because, fortunately, not at our institution, but some patients who had very extensive disease, I mean they had lymph nodes the size of a large grapefruit all throughout their body, and, unfortunately, they were on a dose of the medicine and experienced such a dramatic tumor lysis that the contents of the cell released some cells into the blood. And that's really causing problems because, as you know, the insides of the cell are much different than what you have outside the cell. The high potassium levels. Exactly. And that's something that we have to be very careful about. So with the subsequent trials that were opened up after those occurrences, we actually have been monitoring patients very carefully to make sure that they don't have this. And, fortunately, we haven't seen that since we've been implementing steps where we bring the patient actually in the hospital for close monitoring, and I think that's really helped a lot. And have you changed the dosing in terms of how you escalate the dose? Yes. We start with very small doses and take baby steps up and we find the right dose for the patient. And I think at that level and monitor very closely for the tell-tale signs of tumor lysis. The unfortunate thing about tumor lysis is that patients don't have any symptoms at all until you get into disastrous consequences. So the patients may not feel badly at all and so you have to monitor this by taking blood samples. Are patients still required to be hospitalized for taking the pills? No. Actually, when they get acclimated in fact, when these two events occurred, one on the East Coast and one in the Northwest, the trials were put on hold, but we were allowed to continue therapy of our patients. And I had one patient who achieved this MRD-negative complete response in January of last year when the clinical study was put on hold. He did not want to stop therapy, because he felt that if he stopped he might not be able to get back on therapy. And then after numerous discussions with the FDA, the trial was able to open again. And so the trial when it opened in the summer of last year, in 2013, we did another marrow biopsy, and he still was MRD negative. So he elected to stop, and that's when he discontinued therapy. I've been following him ever since, and so far he's not shown any evidence of recurrent disease. And there was another trial that you were involved with, ABT and rituximab. That's correct, yeah. ABT and rituximab and ABT and obinutuzumab (Gazyva), which is a third-generation rituximab, which has been glycoengineered to be even more effective. And there's some new data presented here at ASCO. Can you bring us up to pace on those? Well, I think what we're seeing is that they are experiencing, first there's a complete response rate which is respectable. In terms of getting rid of MRD, we would wish it to be 100 percent, but right now we're seeing in about maybe 25 percent of
That's amazing compared to some of the other oral medications. Yes, and why isn't it affecting 100 percent? Those are things we need to find out. And I think that's why even with these advances again, I think it's going to take a combination of approaches, maybe the monoclonal antibodies combined with ABT-199 or different combinations of drugs combined, different dosing regimens. There's a lot of work that needs to be done. I think it would be a mistake right now to say, gee, all this great therapy that's out there, we're done. We're not done. We actually have still a lot of work to do. And I think it's very important, and I don't think we should rest until we can say that this CLL is put into the rear view mirror, and patients can go on their lives. It's embarrassing we can't cure it outright. Any final thought from ASCO 2014 you want to share? I think ASCO 14 here is always good. It's good to see leukemia having some spotlight. But I do say it's exciting from the standpoint of this protein that I mentioned to you before, the ROR1 protein is that we are actually finding it not just on CLL cells, but we're finding it on a variety of other cancer cells, lung cancer, prostate cancer, ovarian cancer. Wow. And it seems to be But only on cancer cells, not on lung tissue, not on Only on cancer cells. prostate tissue, yeah. It seems that it's entwined with the process of metastasis and growth of tumors, which is really very interesting. It's gotten me to think about CLL differently because CLL is really an indolent disease hopefully, primarily but it's also one of the most metastatic diseases on the planet because at diagnosis it's in every lymph node, it's in the bone marrow. So these cancers that have a predilection for metastasis may be expressing this protein. Wasn't it isn't it an embryonic protein? It's an embryonic cell, yes. So that kind of gives a hint that there may be
Yes, I think you know, cancer is not an alien from outer space. Cancer is us. And so what I think cancer cells do is they go back to an early program, a tune that we've played before. In other words, when you're developing in the embryo you're a ball of cells, and, fortunately, some of those cells have to metastasize to other parts of the developing embryo to form a nervous system or to form the digestive system. So metastases is inherent in our origin as an organism. And what cancer cells do is they start to play it again and to the detriment because we're not an embryo anymore. But I think if we can hone in on those signals that are used during that process, we might be able to potentially cure cancer in a way that might be far reaching, more than just for the treatment of CLL. I always learn so much when I talk with you, Dr. Kipps. Thanks so much for your time. Thank you very much, Brian. Thank you. Dr. Brian Koffman at ASCO 2014. Exciting time in the world of CLL Thank you very much. Good. Boy. That was exciting. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you.