Dr. Melani discusses the latest updates from the VVIP, VIPOR, and VIPOR-P studies, which are clinical trials for non-Hodgkin's lymphoma. The goal of these studies is to improve the outcome for patients with relapsed or refractory lymphomas by using targeted therapy combinations. The targeted therapies block specific proteins that cancer cells need to grow and survive. The conversation also discusses these three clinical trials' design and treatment protocols.

Kat: Welcome to today's episode of Health Tree Podcasts for DLBCL and Follicular Lymphoma, a show that connects patients with lymphoma researchers. I'm your host, Kat Richardson. Thank you to our episode sponsors, Regeneron and Bristol Myers Squibb for their support of this Health Tree Podcast show. Before we get started with today's show, I'd like to mention two upcoming events that we will be hosting:

A pre-recorded podcast will be published May 3rd.
In this podcast, Dr. Strati will discuss DLBCL and follicular lymphoma clinical trials at MD Anderson. Please submit all questions by April 25th. 
And on May 22nd, we will have a live webinar with Dr. Miklos discussing CAR T cell therapy advances in large B cell lymphoma. To register for either of these events or submit questions, you can visit https://healthtree.org/dlbcl/community/events

With that out of the way, we can begin today's topic. The National Institute of Health in Bethesda, Maryland conducts thousands of clinical trials at any given time. Currently, Dr. Melani is the principal investigator for three crucial non-Hodgkin's lymphoma trials. He is here to discuss the latest updates from the VVIP, the VIPOR, and the VIPOR-P studies.

We are so pleased to have you here with us today, doctor. And before we begin our discussion, let me provide a quick introduction for you.

Dr. Melani is a staff clinician and a clinical research, and a clinical research specializing, I almost set up, I'll just cut it out. Dr. Melani is a staff clinician and a clinical researcher specializing in lymphoma. His areas of interest include the use of novel therapies and drug combinations for the treatment of lymphomas, as well as novel therapies of molecular monitoring of diseases and response to treatment, such as circulating tumor DNA. Thank you so much for joining us today, doctor.

Christopher Melani: Thank you for having me.

Kat: So my first question I want to ask you is kind of to get to know your role at the National Institute of Health. With this job, do you see patients? Do you only do research? Do you only see study patients? What is your day-to-day job like?

Christopher Melani: Yeah, so the National Institute of Health, we're part of the intramural program of the NIH and NCI, or National Cancer Institute. And I actually came here in 2014 as a clinical fellow and stayed on as staff clinician. So I'm going on 10 years here at the NIH Clinical Center. So we are the largest clinical research center, I believe, in the world. So all patients that we see here at the clinical center are study patients that are treated on one or more of our clinical trials. And I actually work as a clinical investigator in the lymphoid malignancy branch. So yes, I do see lymphoma patients both in the clinic as well as in the hospital. But again, all of them are on a clinical trial, which is unlike other academic institutions where there's a mix of both trial patients as well as standard of care patients getting treated with the standard approved therapy.

Kat: Okay, and do a lot of these patients come from far away or is it just local mostly?

Christopher Melani: Yeah, so I think a majority of our patients do come from the local DC, Maryland, Virginia area. But given that we are federally funded, we don't take health insurance and we do have the ability to bring in patients from all across the country. Since this is federally funded through the United States, we actually do provide travel reimbursement and assistance for patients traveling here within the United States. However, those patients who are outside of the United States, we can only provide travel reimbursement for those from the nearest port of entry into the United States. So a majority of our patients do come from the U.S. but from all over the country, including Seattle, Washington, New Mexico, California, Colorado, not just the D.C. metro area here.

Kat: Okay, that's very interesting. Thank you for sharing that. Let's start mostly our topic about discussing targeted therapy combinations in general. So can you give us kind of a history of this treatment type? What are targeted therapy combinations? And how do they work? What do they target?

Christopher Melani: Sure, so targeted therapies have been around for many years now. They generally refer to the class of medications that are oral, mostly oral medications. They're generally small molecule inhibitors that, unlike chemotherapy, their mechanism of action is actually inside the cancer cell where they typically block key specific proteins that these cancer cells need to grow and survive. This is unlike chemotherapy or cytotoxic chemotherapy, which in general is intravenous infusions that non-specifically disrupt DNA of any rapidly dividing cell, and also different from other immunotherapies where it either harnesses or alters the immune system to try to target the cancer cell. So these targeted therapies have been around for many years.

Some of the drugs that we're using in our combination studies have been approved for one or more B-cell cancers for over a decade or so. The issue though, whenever these drugs are approved, they're generally given as a single agent or sometimes doublet therapy and often indefinitely, which can lead to toxicity both financially as well as medically.

And at least in the case of aggressive lymphomas, they rarely lead to deep remissions or very durable remissions when given by themselves.

Kat: Okay, and so when are these therapies used versus other types of options?

Christopher Melani: Yeah, so typically, at least with aggressive lymphoma, with diffuse large B-cell lymphoma being the most common, fortunately, we can cure a significant proportion, about 65 to 70% of patients overall with frontline chemoimmunotherapy. When those patients, however, either relapse after chemotherapy or are refractory to chemotherapy, generally their options are pretty limited and they have much poorer outcome.

Certain types of immunotherapies have been approved for these cancers in the relapse refractory setting, although they don't cure all patients. So that's usually when these targeted therapy combinations are typically used in the relapse refractory setting after chemotherapy and sometimes after some of these approved immunotherapies. Although again, some are approved as monotherapy for use in B-cell lymphomas. These combinations are relatively new, and especially those that you'll see with the VIPOR and the VIPOR-P studies, where we're now getting to the point of combining two or sometimes three of these targeted agents together. But this is really a novel approach where we simultaneously targeted five different survival pathways in B-cell lymphomas in both the VIPOR and then six in the VIPOR-P regimen. So there's a little bit of a new approach to using these agents in combination, again, to try to induce these or drive these lymphomas into a deeper and more durable remission. And unlike the practice that's given as monotherapy, where they're given every day, and definitely as long as a patient's tolerating them until or the disease progresses on therapy,

We tend to give these combinations in cycles similar to chemotherapy. And for a fixed duration, we stop therapy. We don't employ maintenance or prolonged indefinite therapy because of this potential risk of long-term toxicity, as well as with continuous use inducing treatment resistance for some of these agents.

Kat: Do you have any examples of like the current standard of care for targeted therapy combinations in either follicular lymphoma or DLBCL?

Christopher Melani: Yeah, so in Diffuse Large B-cell Lymphoma, we performed one of the first Phase 1-2 studies using ibrutinib monotherapy, for example, in patients with Diffuse Large B-cell Lymphoma. And this study that was published in Nature Medicine back in 2015 showed that a significant proportion of DLBCL patients did respond to single-agent ibrutinib.

It was about 25% overall. In different subtypes, it was as high as maybe 37%, 38%. However, whenever you gave ibertinib alone, it was only about one month or so before the lymphoma started to grow and progress on the therapy. No targeted therapy is currently FDA approved for use in diffuse large B-cell lymphoma. However, these treatments have been used in the relapse refractory setting in certain patients, including ibrutinib in the non-GCB or ABC subtype of diffuse large B-cell lymphoma, as well as lenalidomide, which has been used across all subtypes of diffuse large B-cell lymphoma. In specifically in follicular lymphoma, however, lenalidomide in combination with the rituximab or the so-called R-squared regimen has been FDA approved for use in patients with follicular lymphoma after two or more prior therapies based on randomized studies showing a benefit of the combination of the two agents compared to either rituximab or lenalidomide alone. So there are certain lymphomas where these targeted agents are approved either as monotherapy or in combination. But again, there is none of the combinations or monotherapy targeted agents are approved in DLBCL. Although some are recommended based on studies and national guidelines like NCCN guidelines in the relapse refractory setting.

Kat: Perfect, thank you for that explanation. I think now let's go into talking about the background of each study. So with these three studies, kind of what, why are they being done? What are the flaws or challenges currently in this patient population and the standard of care that would justify the need for these studies to be done?

Christopher Melani: Yeah, so at the National Cancer Institute, we've been studying diffuse large B cell lymphoma for decades in our group. And through our lab, we've elucidated some of the key biologic pathways that are crucial for survival in these diffuse large B cell lymphoma cases or cell lines and models.

Why we're doing these studies, as I mentioned, although about 65, 70% of patients can be cured with frontline chemotherapy, those patients who aren't cured or are a refractory to chemotherapy have poor outcomes. And although certain approved immunotherapies like CAR-T have improved that outcome; still only around 40% or so of patients are cured with CAR-T leaving the other two-thirds of patients that need additional therapy. So we knew in these relapsed refractory, mainly aggressive lymphoma patients, better therapies were needed to improve overall outcomes in terms of survival. Based on that original phase two study that I mentioned using ibrutin and as monotherapy, we knew that these targeted therapies were active in relapsed refractory diffuse large B-cell lymphoma. However, as I mentioned, the durability of the response or the deepness of the remission was not that good, and it only measured in a matter of a few months when given as monotherapy. And in fact, that has been the case across all these agents, not just Ibrutinib, but also has been seen with other targeted therapies like lanolidamide and venetoclax. So we were fortunate enough to have a mechanism in the lab to be able to do high throughput drug synergy screens to look at thousands of different molecules both FDA approved as well as in investigation to see which combinations of targeted agents could synergistically kill lymphoma cells in the lab. And some of the top three molecules that stood out for synergizing with agents such as ibrutinib, where the BCL2 inhibitor, venetoclax, as well as the immunomodulatory agent, lenalidomide. We also hypothesize that giving all of these targeted therapies together indefinitely would lead to increased toxicity and potentially increasing the risk of development of tumor cancer resistance.

So we actually modeled the VIPOR regimen and the VIPOR polar regimen after cytotoxic chemotherapy where we gave Non-continuous dosing of the study drugs. So two weeks of study pills one week break for a fixed duration of only six cycles or 18 weeks, and stop and the reason we did that again was to reduce toxicity, reduce the development of treatment resistance and try to drive the lymphoma into a deep and durable remission. So we also added corticosteroids to those targeted agents because they also affect B cell receptor signaling, which is important for certain types of diffuse large B cell lymphoma. And we did add the type 2 CD20 antibody, Obinutuzumab, as another method to facilitate the immune response to the malignant B cell direct cytotoxicity as well as a recruitment of the innate immune system. And those preclinical studies led to the original VIPOR study. And actually in the VIPOR study, we showed overall that it was safe and very effective. And it was so safe that we even further built upon that through the addition of the antibody-drug conjugate polatuzumab for the VIPOR-P study. 

The VVIP study is a similar approach in that it combines three different targeted agents in patients with relapsed refractory lymphoid malignancies. However, it's a little bit of a different target with the VIP152 or the Enitociclib, which is actually what's called a CYCLIN-D, a CDK, a CYCLIN-dependent kinase 9 inhibitor, which actually blocks the transcription of certain key transcription factors and proteins that these lymphomas need to grow and survive, such as MIC and MCL1. So by blocking these survival transcription factors with the CDK9 inhibitor, and then also blocking the pro-survival protein, BCL2, through the venetoclax that we give on there, it's hitting different pathways separate from some of the ones that are targeted in the VIPOR and VIPOR-P regimen. So similar design in that we're giving three agents in a non-continuous fashion for fixed duration of a different target. And again, all of these treatments are really designed to try to improve the outcome in these patients with relapse refractory, mainly aggressive lymphomas that really haven't been cured with chemotherapy. and many of them are either refracted to or relapsed after some of these approved immunotherapies, like CAR-T treatment.

Kat: Perfect. And a question I have specific to the VIPOR-P study when I was reading through the study itself. Can you explain the difference between GCB and ABC when they talk about that in there?

Christopher Melani: Yeah, so for several decades now, we actually learned that diffuse large B-cell lymphoma, although it's the most common aggressive B-cell non-Hodgkin cell lymphoma, it's actually multiple different diseases when you dissect this from a molecular level. So some of the earlier studies using gene expression profiling actually divided diffuse large B-cell lymphoma into three main subtypes. One that was called GCB, or germinal center B-cell-like subtype, and another called ABC, which is an activated B-cell subtype. And there was a third category of type III, or what we call unclassified diffuse large B-cell lymphoma. And what this really refers to is where, where in the life cycle of a normal B-cell as it comes out of the bone marrow, goes into the germinal center of the lymph node and then is exposed to antigen and comes out as an activated B cell, where in the normal life cycle did it break off and become a malignant lymphoma. And the reason that's important is because these lymphomas possess certain genetic alterations that are characteristic of those types of either germinal center or activated B cells.

With some of these agents that are used in VIPOR and VIPOR-P, such as ibrutinib and lenalidomide, they affect B-cell receptor signaling at different points along the pathway. And one of the hallmarks of the activated B-cell subtype ABC subtype of diffuse large B-cell lymphoma is chronic active B-cell receptor signaling. So we hypothesize that some of these agents in VIPOR such as ibrutinib and lenalidomide would be more active in patients with the ABC subtype of diffuse large B-cell lymphoma. And that in fact was the case where about 62% of patients with the non-GCB or ABC subtype of diffuse large B-cell lymphoma had a complete response with 39% of these patients remaining in durable remission at least two years. And that was compared to no complete responses. And only 33% of patients having a partial response with VIPOR and a two-year progress-free survival, only 8% in those patients with the germinal center subtype of diffuse large B cell lymphoma. In the VIPOR-P study, we've also found over time with certain studies such as the Polarik study that led to the approval of Polituzumab in combination with R-CHIP versus R-CHOP. Polituzumab is more active also in the ABC subtypative usage B-cell lymphoma. So in fact, on our VIPOR-P study, we actually saw a slightly higher preliminary complete response rate that we're exploring in a higher number of patients. And in fact, the VIPOR-P study at this point in time is expanding only into the ABC or non-GCB subtype of diffuse large B-cell lymphoma. 

So it is important, the GCB and the ABC distinction, to better understand the biology of the actual disease and help try to predict whether they will respond preferentially to some of these targeted agents. And at least so far with both VIPOR and VIPOR-P, it's been much more active in the ABC or non-GCB subtype compared to the GCB.

One class of diseases, aggressive lymphomas, that's been recently described in both the World Health Organization classification as well as the International Consensus Classification in Lymphoid Malignancies is this high-grade B-cell lymphoma with MIC and BCL2 translocations, or double-hit diffuse large B-cell lymphoma. We didn't previously hypothesize that it would be that active or respond that well to VIPOR or VIPOR-P therapy, but actually quite unexpectedly we had very good results with over half of patients with this high-grade B-cell double-hit Bcl-2 having a complete response and almost 50%, about 47% remaining in durable remission with progression-free survival of 47% at two years. So quite unexpectedly, the double-hit patients did benefit to VIPOR.

They typically are of the GCB or germinal center subtype of diffuse large B-cell lymphoma. We think that that's probably due to the BCL2 inhibition with the venetoclax, but we're exploring that further in the lab to better understand why they respond so well. With the polatuzumab, we haven't seen that as active in these double-hit patients, so the addition of polatuzumab to VIPOR, although it seems like it may improve the outcome of patients with the ABC subtype, it doesn't seem to really affect or improve the outcome in these double hit patients.

Kat: Perfect, thank you for that. So for those of us who are less familiar with clinical trials, can you give us kind of what the main goal or objective of each of these studies are? So what needs to be proven in order to have them, the drug regimen approved?

Christopher Melani: Sure, yeah, so all of these three studies that I'm describing today are phase one, two studies. So in the phase one portion of the study, the goal is really safety. We're trying to assess the safety of the combination because this is the first time that all of these drugs, five or six drugs, have been given in patients and patients with lymphoma. They're all at different stages in development.

The VIPOR study has completed the phase one portion of the study where we showed that the combination of all five of the VIPOR drugs was safe. And in fact, it was very active. So we've actually enrolled and even completed some of the phase two components of the study in different certain lymphoma subtypes. In the phase two portion, the goal really is to see how active and effective the treatment is in terms of how much does it shrink down tumor masses and how many patients or what percentage of patients will it make the tumors go away completely? We've actually completed the phase two enrollment in the VIPOR study for both diffuse large B-cell lymphoma as well as follicular lymphoma. And we're actually currently in the phase two expansion for patients with mantle cell lymphoma. So we've identified how safe and active it is in both follicular and and diffuse large B-cell lymphoma. We've identified the safety in mantle cell lymphoma, but we're still enrolling patients on the VIPOR study with mantle cell lymphoma to see how active it is in this particular lymphoma subtype. With the VIPOR-P study, it is also again a phase one to study, and we have completed the phase one portion of this study and showed it to be as safe too as VIPOR. And we really didn't see any significant additional toxicity that we'd expect. Some of the additional toxicities of Polatuzamab you'd look out for are things like peripheral neuropathy or worsening in terms of your blood counts, in terms of your white count with a neutropenia or leukopenia. And really compared to VIPOR, we saw minimal additional toxicity that was with the addition of the Polatuzumab. So right now, the Polatuzumab is in phase two expansion.

And as I mentioned earlier in the discussion, the polotuzumab as well as the VIPOR regimen both appear to be most active in this non-GCB or ABC subtype of diffuse large B-cell lymphoma. So we're currently in the expansion phase, the phase two expansion phase, to see just how well the VIPOR-P treatment works in patients with non-GCB DLBCL. We're hoping to get enough numbers to be able to compare our data with the VIPOR study alone to really see, are we getting a higher rate of complete remission in these patients with non-GCV DLBCL with this addition of polatuzumab compared to those who are just getting VIPOR alone. 

With the VVIP study, that's our most recent study, it's also a phase one, two study looking at both safety and and how well the treatment works in patients with relapsed refractory aggressive lymphomas. However, we are still in the phase one portion of that study. So the phase one portion of that study is testing four different dose levels of the combination of the pill, venetoclax, as well as the infusion, VIP152, and it's a fixed dose of the prednisone, which is the P portion of that. We're completing the second dose level out of four. So far we've not seen significant toxicity with the two lowest doses of those two drugs when given in combination with all three medications together. But with the next two cohorts of patients, we'll increase the dose of the VIP-152 and then we'll finally increase the dose of the venetoclax to the full dose to see if this dose is safe. Once we show safety in the phase one portion of that study it will expand into phase two and three different subtypes. One with this non-GCB diffuse large B-cell lymphoma, another with MIC rearranged diffuse large B-cell lymphoma or double-hit diffuse large B-cell lymphoma. And there is also a separate cohort for patients with peripheral T-cell lymphomas that will be assessed to see how well it works. And we have certain parameters within each of those three cohorts to say, if we think that it's working well or not within each of those different diseases. 

So all three are similar in terms of being phase one to studies that are looking at the safety and efficacy of all the regimens, but all three are in different stages of development and different phases.

Kat:
Perfect, thank you for explaining that so well. So I've noticed there's a lot of similarities between these studies. And you might have already said this in your description, but what are the major differences between these three?

Christopher Melani: Yeah, they're pretty similar in design. And again, all of them involve a combination of targeted therapy pills, as well as either an immunotherapy or targeted therapy infusion. So with the VIPOR and the VIPOR-P studies, the infusion of the antibody for VIPOR or the antibody and the polatuzumab, the antibody drug conjugate polatuzumab,

Those are given on the first two days of every cycle and a cycle is three weeks duration. The pills for both those studies, the study medications, the oral medications of vanetoclax, ibrutinib, prednisone and lenalidomide, or Revlimid, those are given for two weeks of the cycle with a one week break of all different medications. So when patients come into trial, they typically come, they see us in clinic.

They get their scans, they get their blood tests. We say they're good to go for treatment. And then again, two days of infusion, two weeks of pills, one week break, and then that's a cycle. And again, for both of those studies, we give a total of six cycles or 18 weeks, which is just over four months in total duration. For the VVIP study, again, it's a little bit different because instead of five or six agents, it's three agents. Two of them are pills, oral pills. One of them is an IV infusion. Similar to the VIPOR study, it's a combination of the pills and the infusion, but unlike the VIPOR study, the pills are given for 10 days duration rather than 14. And the IV infusion is given once a week for two weeks and then one week break. So essentially patients get the infusion on day two and day nine of each cycle and then they take the pills, venetoclax and the prednisone for days one to 10 of each cycle, and then they get essentially another 11-day break and a cycle is total of 21 days. That particular study gives up to 12 cycles every three weeks, so it's just over about eight months or eight and a half months of total duration, and if a patient achieves remission after cycle six or cycle 12, they are able to stop after those 12 cycles of initial therapy. If they're not in remission, but they're not progressing, and they're tolerating the therapy well, the study does allow up to 24 total cycles of therapy, but no patient, regardless of response, gets more than 24 cycles of treatment.

So similar in terms of a combination of pills, oral pills as well as IV infusions, but similar in terms of the total duration of cycle being every three weeks, but a little bit different in terms of when the infusions are given and how many days the oral medications are given.

Kat: Okay, that's helpful. So for the patients that end up on these trials, what is their follow up? Like how what kind of commitment is that? How often do they have to get tested or seen by a physician?

Christopher Melani: Yeah, so typically, with any clinical trial, most of the testing is pretty busy and focused upfront to get them on the study. So all patients undergo baseline testing, which typically includes scans such as CT scan and PET scan, bone marrow biopsy, as well as a biopsy of any accessible tumor to help confirm diagnosis and for research. And when they're on the study, typically, they see us at minimum once every three weeks prior to each treatment cycle. And then when treatment is completed, then patients typically see us in clinic for follow-up. And the follow-up varies based on the particular study, but in general, it's much more frequent right after treatment is completed. So generally, on the order of every three months for the first year post-treatment and then spaces out over time to every four months for the second year, six months for the third year, and then once a year after a patient hits the third year. Those follow-up visits are generally outpatient in the clinic just for blood work, CT scan to ensure that they're still in a remission, and then they follow up again in anywhere from three to 12 months.

Kat: Okay, and accessibility wise, I think you mentioned earlier that these studies are technically international, but are there locations that have more or less ability to participate in these studies?

Christopher Melani: Yeah, so just to clarify, these particular studies, the VIPOR, the VIPOR-P, and the VVIP studies are currently only at the National Cancer Institute in Bethesda, Maryland. So they're not anywhere else within the United States or internationally, which is different than some other trials. That being said, we are in development of an expanded trial for the VIPOR study in patients with non-GCb diffuse large B-cell lymphoma, as well as this high-grade B-cell lymphoma double-hit B-CL2 that is currently in the later stages of development between the Extramural National Cancer Institute, as well as our ECoG cooperative groups. So that will open up the VIPOR study to multiple sites across the United States for enrollment in patients with relapse refractive diffuse large B-cell lymphoma.

In patients with mantle cell lymphoma, we have also been in discussion with our European colleagues in the European Mantle Cell Lymphoma Network, and we are also in the development of opening up, we're trying to open up the VIPOR study in patients with relapsed refractory mantle cell lymphoma throughout the different centers in Europe. But again, currently, all three of these studies are single center only here at the National Cancer Institute in Maryland.

Kat: Okay, thank you for clarifying that. That makes a lot more sense. So, is that typical with phase one and two studies that they're just center that in that specific center and they're not even nationwide?

Christopher Melani: Yeah, I was going to say that. I would say that's probably typical and one of the places that we as the intramural NCI excel at developing these novel combination new treatments. And we typically iron out the safety and the activity here in our single center study sites. And then once we see that it's very safe and active, then we try to export that.

throughout the United States and the world. We typically don't do big randomized phase three studies within the intramural NCI here in Bethesda, Maryland. And that's where we really turn to our extramural NCI program, as well as our cooperative groups to help with that development in a multi-center study.

Kat: Okay, that makes a lot of sense. So next I'd like to kind of go into a quick discussion about the drugs that are used in each of these. Mostly just maybe the drugs that cross over into all the studies, but I know there's a lot of them, like Prednisone, Ibrutinib, Revlimid. So if you wouldn't mind just kind of talking a little bit about the history of them, at least the main drugs.

Christopher Melani: Yes, as I mentioned, all of these drugs aside from the VIP152 have been used or are FDA approved for one or more types of B cell malignancies. Both ibrutinib and lenalidomide, probably one of the first approvals in the United States was in mantle cell lymphoma patients where it's used again as a single agent usually indefinitely as long as the patient's tolerating therapy and not progressing. Both the ibrutinib and the lenalidomide as well as the prednisone, as I mentioned, target different points along this B cell receptor pathway. And what the B cell receptor pathway is, so all of these cancer cells need to signal from the outside of the cell into the nucleus where the DNA is housed in order to tell the cell it needs to grow and divide and survive.

Ibrutinib, lenalidomide, and prednisone all affect that B cell receptor signaling on various points along the pathway with the thought that if we can block multiple pathways, we can really downregulate that signaling and cause these cells to essentially die. The BCL of the venetoclax medicine is a little bit different. It affects something called apoptosis, which is basically self-death of these cancer cells.

So the Bcl2 protein, which is inhibited by venetoclax, is actually a molecule that tells the cell to survive and not to die. So by blocking that protein, you can actually induce cell death for these cancer cells. And as I mentioned, the Obinutuzumab in this particular treatment is an antibody, so it's actually a type of immunotherapy that targets a protein that sits on B cells called CD20.

And by targeting that, it can directly induce death of the cancer cell, but it also can recruit the body's own immune system to fight and kill off the cancer cell. In terms of the VIPOR-P study, it uses all these agents and adds something called polietuzumab. And what polietuzumab is, is an antibody drug conjugate. It is approved for diffuse large B-cell lymphoma, both in combination with chemo in the front line as a first treatment as well as in combination with chemo as a second or third or later line treatment. And what it does, it's an antibody drug conjugate. So similar to the abilities of an antibody, it binds to a protein on the cancer cell, something called CD79B, and it actually internalizes the antibody-drug conjugate the chemotherapy which inhibits the microtubules that are required for these cancer cells to grow and survive. So you can think of it as being one of the targeted chemotherapies where that chemotherapy payload is delivered directly into the cancer cell. In terms of the VVIP study that uses venetoclax and prednisone, which I mentioned before with the VIPOR studies affects B cell receptor signaling as well as survival pathway through this Bcl2 protein. The CDK9, like I mentioned earlier, is a little bit of a different mechanism where it actually inhibits the transcription of some of these RNA molecules that are needed to make some of these key proteins, such as MIC and MCL1, that some of these cancer cells depend on to survive those proteins and transcripts and in inducing the cell death, you can have two different mechanisms to try to kill these cancer cells. And that's important and was really designed for these double-hit patients because when we talk about high-grade B cell lymphoma double hit, the two hits are really the MIC gene, which MIC is a gene, it's an oncogene that induces cells to survive. And BCL2 which is often, which is the other hit in double hit DLBCL is that gene that I mentioned induces cell or causes cells to survive. So by blocking the MIC with the CDK9 inhibitor, and then also blocking the BCL2, the survival signal with the venetoclax, we can really knock out both of those hits that are dependent upon in these double hit diffuse large B-cell lymphoma cases.

Kat: And you don't have to go into detail for each medication in this part, but what are the main side effects or contraindications for most of these medications?

Christopher Melani: Yeah, I was going to say, so you think you hear a lot of these medications. So of course, there's probably a laundry list of side effects. But overall, we were very pleased with how well these combinations were tolerated in patients of all ages on both the VIPOR and the VIPOR-P study and so far in the VVIP study. Unlike standard chemotherapy for that's used in diffuse large B-cell lymphoma and others we saw much less risk of infection and much less risk of febrile neutropenia, which can be life-threatening in patients and require hospitalization and admission for intravenous antibiotics. The most common side effect overall was on the blood counts. So we did see neutropenia as well as low platelets, so low white blood cells and neutrophils, low platelets and low red blood cells, but It was much less than what we expect with chemotherapy, and again, very uncommon to result in any fever or infection or requirements of transfusions. Most of the common side effects the patients experienced were things like diarrhea, occasionally skin rash, and a little bit of fatigue that were generally very mild and manageable things like anti-diarrheal agents, potassium supplementation, IV fluids, things like that. But again, compared to standard chemotherapy, we saw much less effect on the blood counts, much less risk of infection and fever.

Kat: Okay, and I think you mentioned earlier, are most of these drugs orally given or is one or two of them through an IV?

Christopher Melani: Yep. So yeah, for each of these studies, most of the drugs are given oral, so taken by mouth, generally once a day. With each of the studies, there is one or two intravenous infusions, depending on the particular study. So both the VIPOR and the VVIP study have one medication that's given intravenously, whereas the VIPOR-P study has two medicines that are intravenous.

Kat: Okay, thank you. So now I'll just ask a few more questions about the study. In the research so far, are there any obvious trends or results from either these phases or prior phases that you're able to share?

Christopher Melani: Yeah, so far, at least in the VIPOR and the VIPOR-P studies, we've completed phase one and showed it to be overall safe in terms of the combination of the five and six drugs. Within the VIPOR study, we've shown certain subtypes of diffuse large B-cell lymphoma, such as this high-grade B-cell lymphoma double-hit, BCL2, as well as this non-GCB DLBCL appear to have better activity and effectiveness compared to patients who are treated that have this germinal center subtype of diffuse large B-cell lymphoma. And at least in the VIPOR-P study, we're seeing that the effect in these non-GCB patients may be even a little bit higher, but we're still enrolling patients with that type to see if it's significantly better than VIPOR alone. So far with the VVIP study, at least in the first two doses of the study medication in the phase one portion.

It does appear to be safe and well-tolerated overall. We have seen some activity in terms of responses in patients with both double-hit diffuse large B-cell lymphoma and T-cell lymphomas. But again, we're still midway through the safety phase one assessment. So we have more patients to enroll there to further define the safety. And then again, we will expand into phase two to really see how effective it is in patients with lymphoma.

Kat: Okay, and how can you see the potential results of these studies changing the future of lymphoma treatment?

Christopher Melani: Yeah, so we think that this really is a new novel approach to treating patients with diffuse large B-cell lymphoma. And we've been very impressed with the durable activity or the durable remissions that we've observed in certain molecular subtypes of diffuse large B-cell lymphoma to where almost upwards of 40 to even 47% of patients, certain types of patients are in a durable, complete remission where we can't even detect at the molecular level evidence of disease using these measures such as circulating tumor DNA at least two years or more. So we think there are certain subtypes that may be cured. Nonetheless, it is also a very effective regimen across lymphoma that can result in a pretty quick and rather non-toxic tumor reduction that can be used to bridge a patient to other types of standard therapy such as CAR T therapy or an allogeneic bone marrow transplant. But again, in some subtypes, we think it may itself be a potential result and durable.

VIPOR-P, again, we're still waiting to see if this is going to be better than the VIPOR regimen in some of these molecular subtypes, and it's still too early to see what the activity and the safety of the VVIP regimen, but we're continuing enrollment on there. So I think these are a different mechanism, of course, compared to some of our standard approved therapies, chemotherapy, as well as CAR-T therapy. It's a completely different mechanism of action that can be used in patients, either pre or post CAR T therapy. They're now approved by specific antibodies and these can be used pre or post by specific antibody therapy. So definitely a novel mechanism of action.

Kat: In your opinion, what are some expected challenges that you foresee with the phases or the approval of these studies?

Christopher Melani: Yeah, so I think the biggest challenge of course is access to all these medications, right? We get these medications and give them to our patients based on research agreements that we have with the various companies that manufacture these drugs. But of course, to get these medications out to patients in the community and get them covered by insurance companies, we need them to either get FDA approved or incorporated into national guidelines.

Unfortunately, with a study like VIPOR or VIPOR-P, where multiple drug companies are involved, it's extremely challenging to get them approved as a combination regimen through the FDA. So we're hopeful that through the results that we're gonna publish through our existing intramural NCI studies here at the NIH in Bethesda, Maryland, as well as some of these follow-up studies that we're doing at multiple sites throughout the United States through our cooperative groups, that will be enough evidence to show the community that these are a safe and very effective regimen in certain types of diffuse large B-cell lymphoma. And that will allow it to get incorporated into some of our national guidelines, like the NCCN guidelines, so that insurance companies and others will be able to provide payment and coverage of these medications for use for patients in the community.

Kat: And it sounds like they all have more phases that they need to go through. So do you have a general idea of the timeline of when potentially these studies would be finished?

Christopher Melani: Yeah, so as we mentioned, they're all in different stages of development. So in terms of the VIPOR study, we are still enrolling patients with relapsed refractory mantle cell lymphoma. So that will likely be open to patients with mantle cell lymphoma for the next year or two until we'll finish a accrual for that. With the VIPOR-P study, we're in the phase two expansion in patients with non-GCB relapse refractory diffuse large B-cell lymphoma likely too will be open for this patient population for the next year or two. In terms of the VVIP study, we're still very early on in the treatment, so we're still in the phase one. So we will expect to finish the phase one portion probably in the next year, and then we'll expand into phase two in the three different subtypes of lymphoma that I mentioned. And again, depending on how active that is in these lymphoma subtypes, that will be open for the next several years for patient enrollment.

Kat: Thank you for that. So we had a few submitted questions. It looks like you've answered some of them. Someone asked what is CD20 positive lymphoma? Can you give us just one more quick explanation of CD20 positive lymphoma?

Christopher Melani: Yeah, so CD20 refers to a protein that sits on B cells, so it's a B cell marker. So when we talk about lymphomas in general, one of our big distinctions, we want to divide them into our B cell and T cell lymphomas. So CD20 is one of the markers that are used to identify a B cell lymphoma, which in general with frontline chemotherapy is much more curable than those patients with T-cell lymphomas. CD20 itself as a protein on these cancerous B cells has been targeted by a number of different types of treatment. Most commonly people think of a Rituximab or a venetismab, which are antibodies that target this. But there is also other things in both research and development that target CD20.

Kat: Perfect. And then another question we had was regarding the VVIP study being for aggressive cancer; what determines if a lymphoma is aggressive or not?

Christopher Melani: Yeah, so in general, aggressive lymphoma has been defined by the biopsy and how it looks under the microscope. So the most common aggressive B cell lymphoma is diffuse large B cell lymphoma, although again this category of high-grade B cell lymphoma double hit can be very aggressive. Aggressive in general, clinically, usually means that it's growing fairly fast where it causes symptoms or problems. You know, within weeks to months rather than some of these indolent lymphomas that can behave very slowly growing for over months to many, many years. Peripheral T cell lymphomas in general as a class tend to be very aggressive overall, although there are certain indolent subtypes, most of them are classified as aggressive. So a lot of this depends on the actual look of the cancer and lymphoma under the microscope.

Kat: Thank you.

Christopher Melani: No, thank you, and I appreciate you having me.

Kat: Of course. And thanks for listening to Health Tree Podcasts for DLBCL and Follicular Lymphoma. Join us next time to learn more about what's happening in lymphoma research and what it means for you. Once again, thank you to our sponsors, Bristol Myers Squibb and Regeneron, who make this event possible. Have a wonderful day.