Join us as we unpack the latest research on glofitamab for mantle cell lymphoma (MCL). We’ll break down the study, compare glofitamab to current treatment options, and explain what this could mean for patients facing relapsed or refractory MCL.

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Let me know your thoughts on today's episode! Share them in a comment or reach out anytime at hannah@healthtree.org. 

Hannah (00:12)
Hi everyone, welcome to today's episode of the Health Tree Podcast for Lymphoma, where we connect patients with lymphoma to the research and information they need to know about. if you've been with us before, welcome back. If this is your first time joining us, welcome. We're so happy to have you join our lymphoma community. My name is Hannah Loosle, I'm your host and the Lymphoma Program Manager here at the Health Tree Foundation.

The goal of this podcast is to make research and new information coming out about your disease easy to understand and easily accessible. If you've ever found yourself overwhelmed by clinicaltrial.gov or medical abstract, we are here to change that.

Stick around until the end of the episode when I'll be back to share my final thoughts on today's interview as well as some additional resources you can dive into related to today's topic.

Today's podcast is pulling from the study to evaluate glofitamab as a single agent versus investigators choice in participants with relapsed refractory mantle cell lymphoma, also known as the GLOBRYTE study. We are going to be joined in just a few minutes by Dr. Portell, a researcher on the study I just mentioned. Before we bring him on, I want to give you all a little introduction.

Dr. Craig Portell holds a clinical faculty appointment in medicine in the division of hematology oncology at the University of Virginia. He practices at the Emily Couric Clinical Cancer Center in Charlottesville and serves as an inpatient hematologist at UVA Health.

He attended medical school at St. Louis University and completed internal medicine residency at Loyola University Hospital. He completed a fellowship in hematology and medical oncology at the Cleveland Clinic. His research interests include determining optimal combinations and timing of targeted agents in B-cell leukemia and lymphomas. And now without further ado, let's bring on Dr. Portell.

Hannah Loosle (01:52)
Welcome Dr. Portell, thank you so much for joining us today.

Craig Portell (01:55)
Thanks for having me.

Hannah Loosle (01:56)
I'm really excited to dig into this study today, but first before we jump in, I like to set the scene for the audience. So let's start with the why behind this study. What problem or issue was seen in the lymphoma space that they were hoping to fill with this study?

Craig Portell (02:11)
So the study is in relapsed refractory mantle cell lymphoma newer agents into the earlier lines of therapy or even studying in that space can be very helpful. So the study is evaluating a new drug in mantle cell lymphoma against what are considered to be some standards in that relapsed space which would be lenalidomide rituximab or benamustine rituximab

Hannah Loosle (02:39)
Perfect. Thank you for providing us with that context. So let's dive into a high level overview of this study. Could you give us a brief description of the study?

Craig Portell (02:50)
Sure, it's a randomized study, so flip of the coin between two arms, glofitamab, which is a bispecific antibody triggers an immune response both normal B cells, but more importantly, the mantle cell lymphoma or other B cell malignancies such as other lymphomas. glofitamab is compared to an investigator's choice of either lenalidomide and rituximab or a standard chemotherapy drug called bendamustine along with rituximab. And the choice between the two is per the investigators and patient's discretion. Lenalidomide is a pill that is supposed to mediate an immune response against the mantle cell lymphoma. And it works very well with rituximab. It helps rituximab really work better than bendamustine rituximab is traditional chemotherapy regimen that we can sometimes use often nowadays in the frontline space, but it can be used in the relapsed area also.

Hannah Loosle (03:48)
Perfect. And what are the goals or objectives of this study?

Craig Portell (03:53)
So the study is looking to enroll about 190 or so patients and looking to see if what we call progression free survival, which is the time that patients, from the time patients start a treatment to the time it either stops working, which we call progression, or if there's an unfortunate death from any event that could be related or not related to the treatment or lymphoma.

So the progression free survival compared between the two arms, the bispecific antibiotic glofitamab versus the investigators choice of the standard treatments.

Hannah Loosle (04:29)
Thank you. And I know you said that glofitamab is a bispecific antibody, but can you describe what glofitamab is, a bispecific antibody a little bit more, and how that works in treating lymphoma?

Craig Portell (04:41)
Sure, so when we say bispecific antibodies, these are small proteins that will connect the cells that are responsible for killing things, including cancer, to the cancer cells themselves. So those cells that kill things are called T cells, and those T cells are then physically brought and activated to the lymphoma cells as well as the normal B cells also. And we know that we can support without B cell, normal B cell production. So the B cell target is CD20 and the T cell target is called CD3 and these are on the surface of the cells so therefore this protein kind of brings the T cells to the cancer cells and then the T cells then kill the cancer cells and that's supposed to be how it works.

Hannah Loosle (05:27)
Thank you for that answer. Bispecific antibodies are really exciting research that we're working on right now. So it's super exciting to hear that this is being done for mantle cell lymphoma. Is there any history of using glofitamab in lymphoma?

Craig Portell (05:36)
Yes.

Glofitamab is actually approved in large B-cell lymphoma. So we use it all the time for patients with relapsed, diffuse large B-cell lymphoma, a different type of non-Hodgkin's lymphoma than mantle cell lymphoma. It's been studied in mantle cell lymphoma also, but we do have lot of experience with glofitamab in B-cell malignancies, specifically the aggressive lymphomas, large B-cell lymphoma in particular.

Hannah Loosle (06:03)
Yeah, thank you for that. And then a big question that patients have regarding participating in clinical trials is what their daily life will look like. So I wanted to dig in a little bit more into what that would look like for this study for any patients who are interested in participating. So how often are tests being done while a patient is on the trial?

Craig Portell (06:25)
So the treatment, most of the tests are being done around the treatment schedule. So if you consider that the treatment schedule for glofitamab is our standard treatments, which would be at all intents and purposes weekly visits for about three weeks and then every three weeks after that.

Most of the other investigations like CT scans, if a bone marrow biopsy is going to need to be performed, would be done around those timeframes. And then the study continues for one year. So that would continue that long, as long as patients are responding well. The other arms are treated just as we do usually. So every four weeks is what the schedule is for both the bendamustine and rituximab and the lenalidomide and rituximab. And again, most of those investigations are done around the time of the infusions.

Hannah Loosle (07:15)
Got it. So what would the what's the treatment schedule and the follow up schedule look like as well?

Craig Portell (07:21)
So the treatment schedules, with the two arms. So glofitamab would be, initially it's a lot of work, a lot of time for about a month. And then it kind of slows down to every three weeks after that, every three weeks. And that continues for a year. And then I believe it's every three months thereafter, so long as there's no progression. And then would need other investigations if that's the case. The other arms, lenalidomide is given for one year and that's a pill that you take once a day for three weeks out of four weeks. So you kind of get a week break. And then the rituximab is given monthly for six months. On the bendamustine and rituximab, the bendamustine is given on two consecutive days, once a month. And one of those days we would also give the standard drug called rituximab. And that would continue with a goal of six times.

Hannah Loosle (08:09)
Okay, got it. And then is this study being done nationwide or is this an international study?

Craig Portell (08:14)
This is an international study. Most of the current patients are from ex-US and we're trying to increase the US enrollment right now.

Hannah Loosle (08:23)
Perfect. And another big question that a lot of patients have so they know if they're eligible for this study is what are the biggest inclusions and exclusions of this study?

Craig Portell (08:33)
So patients have to be relapsed from at least one line of therapy, and they must have been exposed to a class of drugs called BTK inhibitors. So those are pills that people can take continuously. And we're starting to use those drugs earlier in the line of treatment. So most patients that are currently being treated, would likely have a BTK inhibitor in the initial treatment paradigm. Patients treated a few years ago may not have, so therefore they would have had to have been treated with a BTK inhibitor to get onto this study and then ultimately failed that BTK inhibitor, so the disease would have had to come back to be eligible. Patients also could not have seen a CAR T cell therapy or another bispecific antibody.

There's also some, you know, safety inclusion exclusion criteria that to make sure that the drug would be safe to administer and the chemotherapy arms would be safe to consider also. And a patient cannot have known mantle cell lymphoma that's active in the brain

Hannah Loosle (09:32)
Okay, perfect. Thank you for answering that question. So now let's chat about some of the results you've seen so far. So what have you seen in the research so far? Are there any trends?

Craig Portell (09:43)
from our perspective, it's a blinded study and we can't really see any trends at this point because there's no real data to talk about as of yet, unfortunately. So hard to say. We do see that, we know from other patients that glofitamab in mantle cell lymphoma can cause a lot of activation of the immune system, more than we typically see with diffuse large B cell lymphoma.

So we have modified, or the study has been modified to slow the rate of the infusion down. So that does kind of take quite a bit of time in the infusion center. And there's a lot of monitoring for what we call an activation of the immune system, which is called cytokine release syndrome. So we have seen some more serious events in that regard with mantle cell lymphoma, and that is something that we do need to carefully monitor on the study.

Hannah Loosle (10:29)
Yeah, thank you. And maybe for patients who don't understand how clinical trials work, could you explain how a blinded trial works?

Craig Portell (10:38)
Yeah, so I, this is not necessarily blinded to what treatment you're getting. Of course, we're going to know what treatment, what arm you're randomized to. But the results are often not assessed on a routine basis. So as not to impact the results of the study. So if we start to release data that's early and immature, then, then the practice patterns for both physicians and patients may change and then the results of the study may be difficult to interpret. So the study purposely talks about safety. There is a committee that monitors the study for both safety and efficacy to make sure that the study is not going to be not useful for patients anymore. But the global treatment team is not aware of a lot of those background information so as to keep the study, the science behind the study as pure as possible.

Hannah Loosle (11:31)
Okay, that makes sense. Yeah, thank you for answering that one as well. And then are there any expected challenges of trying to get glofitamab approved for mantle cell lymphoma?

Craig Portell (11:41)
Well, know, the cytokine release syndrome issue that I did talk about is something that needs to be thought about quite a bit. So how to mitigate those risks are something that needs to be considered. Otherwise, it does need to show superiority over standard treatments. And we hope that it will. That's the reason why the study is being performed. But we don't

We don't honestly know that right now. I think that's, you know, we're always worried that sometimes we design these studies and they may not work. And we think a novel drug may be effective. And when we do a study like this, it's not. So I think those are always things that we have to consider with any study, not just this one in particular.

Hannah Loosle (12:23)
Yeah, absolutely. And then we had quite a few patients submitted questions that I would like to go through. we had a few about the TP53 gene mutation. So the first question is, is this effective in patients with TP53?

Craig Portell (12:27)
Well, we don't know. We think it could be, and I think that's the promise. But P53 is one of the more common tumor suppressor genes. So when there's mutations in P53, we tend to get more aggressive disease because there's no longer that break on cancer growth and development. And therefore, sometimes it can be harder to treat patients with P53 mutations or deletions.

So using an immunotherapy approach is one way that has been hypothesized to improve the outcomes for patients with P53 mutations. But to be honest with you, I don't think we have any great data to say that that has clearly been a good hypothesis or not. And I think this study is one of those studies that will hopefully help to address that question.

Hannah Loosle (13:21)
Yeah, definitely. And then the next question we have is, where does glofitamab fit into the stages of treatment for TP53 patients?

Craig Portell (13:30)
Well, right now it's not approved in mantle cell lymphoma, but it would be something from a bi specific antibodies would probably be something that we would consider right now in that space of the post BTK inhibitor therapy treatment landscape. So that may be in the second line, that may be in the third line, depending on when a patient may have received their initial treatment and diagnosis of the lymphoma.

So right now it is more of an investigational agent, I would say. But the bispecific antibody class in general is certainly being evaluated in mantle cell lymphoma, probably in the later lines of therapy.

Hannah Loosle (14:09)
Okay, so our next patient submitted question is what kind of side effects have been seen with glofitamab and how are those managed?

Craig Portell (14:16)
Yeah, so the major side effect is obviously the cytokine release syndrome, which can also cause a different type of syndrome that causes some brain issues that we call the ICANS. And essentially the inflammatory cells secrete a bunch of proteins that they're supposed to do because that's what inflammatory cells do that then stimulate more inflammation and more inflammation and more inflammation until we get something that a syndrome that honestly kind of looks like the flu. clearly is not the flu, but it's something that's very, can be very serious with fevers, shortness of breath, lightheadedness, dizziness. Some people can even need to go to an intensive care unit for very careful monitoring of blood pressure. And with the ICANNs, the neurologic toxicity that can happen in combination with the cytokine release syndrome.

Some people can have some confusion. Very rarely do we see things like being ubtonded or just in a minor coma related to that event. The things we do for that are to try to stop the inflammation as soon as possible. So those are things like steroids and a drug called Tocilizumab which helps tamp down the T cell activation, which is happening with Glofitamab treatment and frankly any other immune therapy treatments like CAR T cell therapy or other bi-specific antibodies. So this is a known side effect of this class of medicines as well as the CAR T cell therapy that is approved for mantle cell lymphoma and something that we're very comfortable managing and treating.

Hannah Loosle (15:50)
Yeah, that makes sense. And I was going to say cytokine release syndrome and ICANNs, exactly what you said, are common with CAR T cell and bi specific antibodies. it's, you know, of course, never fun to have side effects, but it's good to know that these have been studied and, you know well how to manage them. So that's great.

Craig Portell (16:09)
Yes.

Hannah Loosle (16:10)
And then you answered this question a little bit already, but just want to reiterate, if a patient has already received CAR T or a bi-specific, can they still qualify for this trial?

Craig Portell (16:20)
Not this particular trial. There is a specific exclusion criteria for both bispecific antibodies and for CAR T cell therapy prior treatment.

Hannah Loosle (16:28)
Thank you. And then our next patient question is, you have to live near a trial site to access this trial or can you travel in just for treatment?

Craig Portell (16:37)
You can travel in for treatment. The treatment does need to be given at a trial site. It cannot be given at a site that's not associated with the study. But yes, you can travel for the study. And one thing I did forget to mention is that patients who are randomized to the standard arm, if there is progression, they can be crossed over to the glofitamab.

So it is possible that even if you get randomized to the standard arm that you could cross over to the glofitamab

Hannah Loosle (17:06)
It's good to know, definitely. And then our next patient question is from someone who has mantle cell lymphoma saying they've been treated with bendemustine, rituximab and zanabrutinib and possibly sonrotoclax Is glofitamab still an option as part of this trial if they were to relapse?

Craig Portell (17:28)
Presumably, because they've been exposed to a BTK inhibitor and have not had a either a CAR T cell therapy or another bi-specific antibody. Sonrotoclax is a new version of venetoclax, if you will. So it's a, it's another BCL2 inhibitor that's being currently studied in, in clinical trials.

Hannah Loosle (17:50)
Perfect, thank you for that answer. And I just want to point out for patients listening, this is not specific medical advice. This is just generally, if you have been treated with these things, it could be an option after you talk to your doctor.

Craig Portell (17:58)
Correct.

Yeah, and there is a strict entry criteria for any clinical study. So sometimes we think a patient may be eligible, that then they end up not being eligible because we find something on the workup in getting into the clinical study.

Hannah Loosle (18:17)
Yeah, that makes sense. And then our last patient submitted question is how does glofitamab compare to CAR T therapy?

Craig Portell (18:25)
That's a fantastic question. So from a practical purpose, CAR T-cell therapy, you know, have to take the T-cells out in a process that we call apheresis and then manufacture those T-cells, genetically modify them, and then re-infuse them into the patient. It's kind of a one-time thing. It's done in one setting, one time interval but does tend to have more intense side effects than most of our bispecific antibody therapies that are currently on the market. And may, and particularly in mantle cell lymphoma, may require some hospitalization and some intense monitoring. Bispecific antibodies, there tends to be a slow ramp up of the infusions, of the dose of the infusions, until you get to that standard dose that then continues for a period of time, usually a year, so long as they are working. No one really has a sense of how if one process works better than another process, if CAR T-cell therapy works better than bispecific antibody therapy. There's no great studies that would suggest one before the other is any better. Some patients can't tolerate CAR T-cell therapy but could tolerate bispecific antibodies because the cytokine release syndrome tends to be a little less severe in bispecific antibodies in general. But we really don't know how they compare to each other or should we do one versus another. They are clearly different in their approach and their treatments and how they're administered. And that may be, as of right now, the biggest way we have to compare them is just how they're administered.

Hannah Loosle (20:01)
That makes sense and it sounds like the side effects and things like that are relatively similar as well.

Craig Portell (20:09)
Somewhat similar, the general gestalt would be that they'd be a bit more severe with CAR T cell therapy, but then CAR T cell therapy is kind of done in three months, whereas the bispecific antibody would continue for longer. So it's kind of more severity of symptoms initially with a one-time treatment versus longer duration of treatment, but symptoms may not be as intense. But similar, but not as intense, if that makes sense.

Hannah Loosle (20:37)
Yeah, that does make sense. And that's super helpful for patients to know when considering different therapies and how each of them will impact their specific quality of life and where they're currently at.

Craig Portell (20:48)
Yeah, it's a very patient-centered discussion about which is better for that particular patient.

Hannah Loosle (20:55)
Yeah, absolutely. And then I had a question about if any patients want to join this trial or really any lymphoma trial at UVA, where can they find more information or who can they get in contact?

Craig Portell (21:09)
Well, all of our trials are on our website. A quick Google search of UVA clinical trials should get to that website. We do have an email list. It's uvacancertrials, all one word, at uvahealth.org. That's an email that will go to our team if there's any specific questions you may have about our clinical trial portfolio or questions about if we have a study that you could consider.

This particular study is on clinicaltrials.gov. That is a very excellent website also to search for your area for any trials that you may be interested in. A simple search on that website, which is maintained and many journals require participation into that database for publication fact, all of the clinical trials are really on that website. A quick search of mantle cell lymphoma, and you can specify your area of the country, will give a list of those studies that are available in your region. The particular clinicaltrials.gov number for this study is NCT 06084936, and there's more details on the website with that number.

Hannah Loosle (22:28)
Thank you for that answer. That's super helpful for any patients who may be interested in this trial.

Craig Portell (22:33)
And I would also say a lot of the societies have very good information about clinical trials. the Leukemia and Lymphoma Society, which is now called Blood Cancers United, Lymphoma Research Foundation, they all have concierge teams that help patients identify clinical studies and can be a good resource for patients to identify what things may be available.

Hannah Loosle (23:00)
Yeah, absolutely. There's a lot of good resources out there for finding clinical trials. And I'll put in a plug for Health Tree real quick. We recently launched our AI clinical trial finders. So for patients who connect their medical records, AI sorts through all the clinical trials that exist and tell them which ones they might be eligible for and which ones are a match. So if that's something you're interested in, Health Tree has those resources as well.

Craig Portell (23:06)
Yes.

Hannah Loosle (23:23)
And then my final question for you today is, you have any final thoughts on the study that you would like to share with our audience?

Craig Portell (23:31)
the study is, it's a good rationale study of a product that we know works well in other lymphomas. We do need to make sure that it can be safe and administer well with mantle cell lymphoma and understand how well it works compared to standard treatments. The crossover is appealing for both, even if the randomization is to the other arm, because crossover can't can allow to get the new study drug. Although we don't know if that's going to be beneficial or not. I think all of those things are important to know. And overall, we think it's a good study to definitely consider.

Hannah Loosle (24:05)
Yeah, absolutely. This has been so informative and I'm really excited to see the research that comes out of this study. And I would definitely love to have you back on in the future to share any updates as they're published. So thank you so much for joining us today, Dr. Portell, and sharing about the incredible work you're doing in the lymphoma space.

Craig Portell (24:24)
Thank you much, thanks for having me.

Hannah Loosle (24:26)
I thought this interview was so interesting. It was really exciting to hear about the potential for glofitamab in mantle cell lymphoma and really dig into all the details of this drug and the trial. If you want to keep learning, we have some additional resources you can look at on the Health Tree website. We have various educational resources about glofitamab and bispecific antibodies, such as some news articles, webinars, and Health Tree University videos.

We also have a connect group dedicated to treatments where you can talk to other patients about their experiences with any treatment, including glofitamab. If any of these resources piqued your interest, I'll link them in the episode description so you can check them out. I also mentioned our AI clinical trial finder during the interview, so I'll be sure to link that in the description as well.

Thank you for joining us today on the Health Tree Podcast for Lymphoma. I hope you learned something new. I'd love to hear your thoughts on today's episode, so share them with me in a comment or send them to me in an email. You can find my email in the episode description. Join us again next time to learn more about lymphoma research and what it means for you.