Movember Session: Outcomes Research – IRONMAN Project - Alicia Morgans and Ian Davis
Alicia Morgans and Ian Davis presented an update on the IRONMAN study, an International Registry for Men with Advanced Prostate Cancer at the Advanced Prostate Cancer Consensus Conference (APCCC). The ultimate goal of this project is to provide the most elaborate description and understanding of patients with advanced prostate cancer. The project includes a description of treatment changes, adverse effects, patient-reported outcome measures, data derived from biospecimen collection and physician completed questionnaires. As of August 2019, there have been 870 enrolled patients, with 30 screen failures, resulting in 792 remaining patients in the study.
Alicia Morgans, MD, MPH is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Professor Ian Davis MB BS PhD FRACP FAChPM is a medical oncologist, cancer immunologist, clinician-scientist, and NHMRC Practitioner Fellow. He is Professor of Medicine, Monash University and Eastern Health, and Head of the Eastern Health Clinical School (EHCS), where he is responsible for all clinical research within Eastern Health through the Monash Eastern Clinical Research Unit (ECRU).
So thank you, everyone. Thank you for being here so early. As we heard, this is a project that's near and dear to many people's heart and as we mentioned yesterday and have mentioned I'm sure over time repeatedly, this is really an effort to include the men who are already being treated for this disease to help learn from them and with them, so that we can do better in terms of their outcomes. So this is just a little bit of an overview of the background. I think we know that this is the most common cancer that's affecting men and certainly this audience does not need to be reminded though we all should think once in a while, at least about this being such a massive cause of death in the ... around the world each year. Certainly there's also a rapidly evolving clinical landscape with therapeutics that are not always clear in terms of how do we best sequence these to get the best outcomes for our patients.
There's also variability in guidelines and certainly in clinical practice around the world, particularly in advanced disease and there is an urgent need for us to identify strategies and treatment patterns that will be optimal for our patients. I think, importantly, we also have a need to ask the patients how they're feeling and ask via these patients reported outcome measures or prompts as well as to really dig into the molecular subtyping of the disease. So IRONMAN was created with several objectives to describe the practice patterns of therapeutic agents for treatment of advanced prostate cancer and to do this on an international scale to assess whether specific treatment patterns are associated with clinically significant adverse events and to evaluate the interactions with concomitant medications, demographic factors, again around the world and to identify associations between treatment sequences or combinations and survival as well as to define the patient experience and identify unmet needs.
Finally, to identify clinical and molecular disease subtypes that predict response to treatments, combinations, and sequences. So this complicated schema is actually not so complicated in practice. This is actually the entire follow up period over the three year time period, which includes the informed consent and identification of patients, a blood sample and physical exam as well as physician questionnaire and physician notes at baseline, and then some follow up over time with patients completing patient-reported outcome measures and having their medications checked at routine intervals as well as assessing for adverse events. The patient population is as you would expect for men with prostate cancer and really it's a focus on hormone-sensitive or castration-resistant disease.
As I mentioned we're going to at ... or we are at baseline collecting medical history, prior treatment information and then we're following these patients over time focusing on patient-reported outcome measures and biospecimen collection along the way. This is just a schematic of the patient-reported outcome schedule that you can see is really at three-month intervals and you can see there's quite an array here to assess. There's also physician questionnaires that are completed by the healthcare provider at baseline and at the first change of treatment and at each subsequent treatment and treatment discontinuation. This is to help understand why physicians are making the treatment decisions that they're making. So why is someone discontinuing treatment? Is it radiographic or clinical progression? Toxicity, patient preference. As I said, we're collecting biospecimens and this includes cell-free DNA, whole blood plasma and they're assessed at enrollment, at 12-month follow-up visit, and at progression. There are multiple working groups and I think there's always an interest in engaging others in working groups that exist and those that are still to be formed.
The PROM or patient-reported outcome measure working group has continued to work. They are actually expanding that window that patients have to complete their PROMS to allow for more flexibility. I think one of the great ways that patients can report the PROMS is actually remotely, which really helps at least in our clinical practice in terms of getting them completed. We're still trying to determine what's going to happen in terms of the PROMS after 36 months. There's also a diversity working group that's trying to strategically identify XUS sites that can be included and as we discussed yesterday, we're exploring new regions in Africa as well as Norway, Japan, France, and the Caribbean and these are some of the lovely folks who are involved in the diversity working group and just to remind everyone, anyone, who's interested I think would be willing or would be welcome to join this group and any of the others.
Biospecimen working group is also continuing to move forward collecting cell-free DNA and continuing that analysis. Here is this lovely group of folks. There are also some sub-studies, so there is a study that's looking at PROMS to try to improve patient outcomes. This is actually just launching. We have just identified the team that's going to be really creating what this sub-study will ultimately do in terms of intervention measures and follow up and there's going to be a call or an expression of interest for people who actually want to open this study as a sub-study within IRONMAN and to proceed forward in answering the questions that are being identified. There's also a quality indicator sub-study and the group has actually been identified. They've already met, convened, and are trying to really define what are some quality indicators for advanced disease that should be measured not just in IRONMAN, but around the world so that we can compare patient populations in clinical care around the world and try to benchmark what is what we expect for care for these men around the world. Now I'll hand off to Ian.
Thanks, Alicia. Alicia has done a great job outlining the design of Ironman, so this is a little bit different. This is obviously not a clinical trial. It's a cohort registry and when we are, when we are consenting patients for this, it's a very different discussion to the usual consent process. So this is not at all about your treatment. You can have any sort of treatment that you'd like. You can be on a clinical trial. This is about listening to you and trying to find out what the patient experience is. So that's why there's a fairly intense schedule for clicking the patient-reported outcome measures and they are quite detailed. We're collecting blood samples at a couple of different time points to future proof the study. We don't have immediate plans for what we're going to do with that work, but that will evolve and it's planned to be done once the funding comes through.
So once we pitch it in those sorts of ways, the patients say, "Okay, yes I'm actually very interested in letting people know my opinion." We use the Movember True North platform, which is easily accessible and most men, even quite elderly men are quite happy to use that electronically and it works very well. So, it's a great initiative and Alicia also alluded to near the end there, the development of clinical quality indicators. I think this is going to be a really important and interesting outcome of these prices. Hopefully, something that we'll be able to standardize and harmonize around the world. So here's where we're up to at the moment. As of August we've got 54 active sites. They are circled in green, 71 pending activation in yellow and as Alicia said we are trying to expand that to bring in additional regions and try to increase the diversity of the platform.
So this is just showing the areas of current activity at the moment. The worldwide initiative, not sure how many animations there are on that slide. So just going to give you a little bit of a snapshot. Obviously not too many results of the study so far, but we can show you some of the data that we have now and this will be a bit of a warts and all presentation. So 870 men enrolled and 792 actually on studies. 78 have already come off study for a range of different reasons. We are running a little bit behind our predicted recruitment, so we are encouraging existing sites to try to look at their processes to try to identify patients more effectively and to bring them on, but also to bring on additional sites to try to get that curve up to the blue one and hopefully well above it.
Here are the demographic factors at the moment with the 870 patients, so pretty much as you'd expect the median age is 70. A vast majority of patients at the moment have come on from the US, but you can see a range of areas there and at the bottom, and this came as a little bit of a surprise to us and I'll come back to it in a moment, you can see the breakdown of disease state at study entries. So over half the patients so far have come onto the study with metastatic hormone-sensitive prostate cancer and only 40% with castrate-resistant disease. Here are the demographic factors and again reflecting the populations that we're looking at. So a majority are white or Caucasian, we have got some African American and similar ethnicity background. They're still very low on Asian participation. I think the diversity working group is looking hard at that and other aspects, the nature of the population. We want this to be representative internationally.
This is now looking at the baseline factors at diagnosis, so this is not at the time of study entry, but when the cancer was first diagnosed, so perhaps a little bit younger than we might expect, but not too far different. PSA below 10. Gleason scores median are fairly high there. I just draw your attention to the figures there in magenta, which came as a bit of a surprise for me. So I've only got 15% of patients at baseline with metastatic disease, but we've got more than half of patients presenting with metastatic hormone-sensitive prostate cancer at study entry. So that came as a bit of a surprise. We would have thought that since we've got so few patients with metastatic disease at diagnosis, more of them would have been picked up in biochemical relapse and being treated and we'd have more M0 going to M1 CRPC.
So that's come as a little bit of a surprise. This is the warts and all bit. This is how we are going at the moment with compliance or completion of the electronic PROMS and in green the numbers as of February, in red as of May, and in blue as of August. So if you're red, green colorblind goes from top to bottom there and you can see there that there were quite a number that had expired. So this is coming down to the logistics of how the study works and how things work out in terms of timing of patient visits, communication, access to the online platform, and how we deal with that for men who don't have that sort of access. So the study is undergoing some amendments to try to simplify this and you can see that we're starting already to improve the return of these forms, which is a very critical part of the project
So we've extended those windows. This is showing how the PROMS are being completed. So again, the vast majority of being completed online, a small proportion by paper. We also offer the participants the opportunity to do it in the clinic with the assistance of the study coordinators. Very few have taken up that option and the numbers dropped down there of course because not so many men or mates made it to the later time points just yet.
Here's where we're going with the biospecimens and this is actually quite encouraging that we are getting good collection and return of the biospecimens. How this is done in a different region varies from region to region, but far we're quite happy with that, and 84% I think is a very good return so far. So in terms of future directions, we've got interest from the investigators to look at archival imaging. You can imagine this and logistic issues in collecting this retrospectively and having it updated and centralized. At the moment, we're not doing that, but we are looking at ways that we might be able to bring that in and obviously that will require protocol amendment. We're looking at several initiatives for how we'll use the translational samples and again, we tried to future proof that as much as possible and for those who are participating or about to participate, there will be another amendment coming out late this year or early next year.