IMPaCT Plenary Session: The Process of Basic Research to Phase III Trials Video (Text Version) - Dr. Tia S. Higano

PCCTC Accelerating the Development of Ipilimumab

Dr. Howard Soule
Our next speaker is Dr. Tia Higano who is a Medical Oncologist at the University of Washington in the Fred Hutchinson Cancer Research Institute in—in Seattle. She is a prolific clinical trialist and an outstanding doctor. She’s going to talk to us more about the clinical applications of this immunotherapy; Dr. Higano.

Tia S. Higano, M.D., FACP; Medical Oncologist, the University of Washington, Fred Hutchinson Cancer Research Center
Thank you, it’s very nice to be here and to be able to give you one example of how we as a group in the PCCTC, I think have really made a major contribution in bringing Ipi(limumab)—I’m going to call it Ipi if that’s okay with you Chuck—Ipi forward for our patients.

You know immunotherapy, if you asked any of us 15 years ago if we thought prostate cancer was going to be a likely target for immunotherapy, most of us probably would have started laughing. But the fact of the matter is there’s a lot of reasons it makes sense. It is—does tend to be a more indolent tumor; it’s not like lung cancer where most of the patients are dead in a year. And it is actually immunogenic. And Chuck has talked a little bit about the preclinical findings—not only mice but in rats and other—other animal models but also in humans. And we know that because recently in the last year, sipuleucel-T or Provenge was approved showing a survival advantage. So there is something going on with immunotherapy in this disease. There are various approaches which we won't belabor today but these include use of cytokines such as GM-CSF, vaccines like Sip-T or Provenge, Prostvac is another vaccine in clinical development and then GVAX and there are others as well. And then the antibody-based approaches which include Ipi and also PD-1.

Now this is a very busy slide but it’s just to show that there—the development of Ipi in prostate cancer was a bit haphazard to be perfectly honest. In our own institution, back in 2002, we participated in a trial that was looking at Ipi alone versus Docetaxel followed by Ipi. It looked—if you look at the far right at the response rate, it was kind of discouraging. Nonetheless within the context of the PCCTC, which the trial started in approximately 2006, we went forward and that’s the trial that I’m going to be discussing very briefly.

So this was a lot more rational than some of the other Ipi trials in prostate. It actually started out as a dose escalation trial where we were using Ipi alone starting at 3 milligrams per kilogram and we escalated all the way up to 10 milligrams and then studied that a little bit further. And then based on the preclinical data that Chuck mentioned to you about the use of radiation and the ability to enhance the effects of Ipi or by releasing—presumably by releasing immune antigens from the—from the cancer killed off by the radiation, we then amended the trial and studied further patients who would get a single high-dose of radiation prior to the administration of Ipilimumab. I’m not saying that right, Chuck; damn.

Anyway we studied this both in patients who had chemo and patients who are chemo naïve. This is just a summary of the waterfall plot of the PSA responses, or I should say declines from baseline. And just in summary, I mean I’m not going to belabor this but you know this is just an immune therapy. Keep in mind that Provenge does not do anything to the PSA. But this particular immune therapy in a significant number of patients did result in a PSA decline whether you were chemotherapy naïve or not and whether you were treated with a single agent or in combination with a radiation.

In addition, the duration of these responses, and actually this is just a snapshot because many of these patients were—still had ongoing responses. Many of these responses were quite durable. And, in particular, and I mean this is—this is why you have to have a group of people who understand the—the toxicities and the potential problems with this kind of agent. The toxicities are real with this agent, particularly so-called IR immune-related adverse events. And these included skin, but intestinal particularly the autoimmune colitis, liver with hepatitis, and so-called endocrinopathies where—such as hyperthyroidism. So these are things that had to be very, very carefully monitored. And during the conduct of this trial we had—I think it was either weekly or ever other weekly—conference calls with the centers participating to discuss the status of each and every one of the patients we had on the trial.

Now this is the star patient and this in fact is a patient from OHSU, Tom Behr’s patient who was a 53-year old man with metastatic castration-resistant disease who came into the trial with a PSA of 655. And this purple bar just shows the duration of the Ipi therapy and the PSA—this is the percent; this is not the absolute value of PSA. It’s a percent. So it was 655—was 100% and you can see during the Ipi therapy, the PSA did drop fairly quickly and—but the other thing and I remember being on the calls talking about this patient because we were all kind of worried; this patient had hepatitis, colitis; he had an abnormal TSH. He had to be hospitalized. Nonetheless over time these problems resolved, and the patient was noted to have partial responses, partial responses, and then ultimately a complete response. This is an example of his bone scan at 24 weeks and you can see the big lesion here in the pelvis. And at 24 weeks it’s gone. Now the—you—I don’t know if we’re going to be talking about some of the other agents that are actually making bone scans better but the fact of the matter is that not many—not many agents do that in this short of period of time, so this was rather impressive to us as clinicians.

So just to review the kind of kinetics, there was a rapid decline in PSA followed by a slow steady decrease, not seen in the other available immunotherapy that we have today. And in addition to the PSA response, because again you know that’s just a number—does that mean anything; well yes. It was accompanied by a definite resist or measurable disease shrinkage in the pelvic nodes and bone scan that I showed you. So the thing is—is that this is all great. If we get a response like this it’s great. But the most important thing is that this response has lasted 4 years. And most amazingly and this is the important thing—I don’t think any patient in this room would deny that this is my take-home message—that this patient, actually Dr. Behr had the balls if you will to take his patient with castration-resistant disease off of his Lupron. And this guy has been off of Lupron for one year with a PSA of 0.2 and but he’s allowed to have some PSA; he still has a prostate. So you know this is a very potent therapy. It’s not—this doesn’t work this way in every patient. This is one patient. But this is the power of the immune system.

So it was based on this Phase ½ trial that we did within the PCCTC that resulted in the—the initiation of two Phase 3 trials because remember this is what we need to go through to get this agent approved. So there’s one trial that started first in patients who had received chemotherapy, and in this trial, patients are being treated according to the radiation regimen that we piloted in the Phase 2 study. So they get either radiation, plus placebo or radiation, plus Ipi. This study is over halfway accrued, aiming for 1,000 total patients. The second study is in those patients who are chemotherapy naïve—is looking at single agent Ipi, and this is not even—not even all the sites are open yet, but still it’s—it’s actually accruing pretty well given that it’s fairly recently opened. And it is—has about 25% enrollment.

So I think hopefully I’ve given you a sense of this one particular agent in which the PCCTC really played a role in accelerating the development of this drug. I think our—the important things we had to contribute were the fact that we—we were a small number of experienced investigators. I mean our own institution worked with this agent since 2002. We were able to maintain very close communications necessary for toxicity and response monitoring because this kind of agent could have been killed very early on had people not known how to deal with it just because of the toxicity concerns. We’ve provided valuable real-time clinical feedback that really would not have been evident to sponsors who were just looking at case report forms that they get either by fax or in the mail. And—and—and subsequently because of our—all of our cumulative involvement within the PCCTC, we were able to help design and lead the current Phase 3 trials that I told you about.

And I think another very important role that the PCCTC has played not only in this—or these I should say but other Phase 3 trials is that we have really pushed the addition of biomarkers into these trials because as we all know as clinical investigators it’s getting harder and harder to do survival trials because of all the new agents that have come up. And so if we have a biomarker that shows that we can use that as a surrogate for survival we’re all going to be better off and hopefully we won't treat patients who don’t need to be treated or who aren't benefiting from the agent. So with that I will leave Dr. Soule to go onto the next topic.