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Expert from Rutgers Cancer Institute Discusses Ongoing Trials in MCL

Danielle Ternyila
Published Online:4:30 PM, Thu May 24, 2018

Andrew M. Evens, DO, MSc
Patients with mantle cell lymphoma (MCL) are very likely to relapse, according to Andrew M. Evens, DO, MSc. The patient population is hard to treat with a lacking number of targeted agents approved in the second-line setting. Rutgers Cancer Institute of New Jersey looks to improve this with several ongoing trials for patients with MCL.

Evens, director of the Lymphoma Program and associate director for Clinical Services at Rutgers, says their goal is to have at least one option for every subtype of lymphoma, including patients with either relapsed or newly diagnosed disease. 

While ibrutinib (Imbruvica) has been approved by the FDA for the treatment of patients with relapsed/refractory MCL, a phase I/II trial looks to combine this with ixazomib to improve outcomes for these patients. Both drugs have shown promise as single agents in previous data.

A phase II trial, EA4151, is currently enrolling at Rutgers for patients with newly diagnosed MCL. Rather than randomize patients to either stem cell transplant or rituximab as in previous trials, investigators will use minimal residual disease (MRD) findings to decide which treatment regimen a patient should receive.

In an interview with Targeted Oncology, Evens discusses the clinical trials that are ongoing at Rutgers. He shares some details of the current treatment landscape and how that will evolve as more data becomes available from trials like those at his institution. 

TARGETED ONCOLOGY: Can you discuss some of the ongoing trials at Rutgers for patients with MCL?

Evens: There are some studies that are ongoing, and then there is a new study. There are always new studies that we are trying to get through the pipeline to get up and running.

There are a lot of new treatments in MCL. I guess you can say that for all of cancer, but there are these novel targeted therapeutic drugs. One is a phase I/II study combining a drug that is already FDA approved for MCL called ibrutinib, with another oral novel agent, ixazomib. That’s a very interesting study because the intravenous form of ixazomib, bortezomib, is also FDA approved. In fact, that was one of the first novel agents approved in MCL.

Some of the issues with bortezomib is it is an injection; it can cause some neuropathy. Ixazomib is basically an oral version, made by the same company. Ixazomib is FDA approved for multiple myeloma, so it is really rational to study the more potent, oral drug. 

TARGETED ONCOLOGY: Is there previous data for the combination of ibrutinib and bortezomib?

Evens: Yes, but, interestingly, there is not a huge amount. I think part of it is because bortezomib is somewhat of an older drug. I wouldn’t call it the oldest drug in the world, but it’s one of the first ones. Even though it was one of the first drugs, and it’s a novel drug and all of that, it just never got a lot of uptake in MCL.

When ibrutinib came along, it was so much more effective. You always have to be careful to compare things, but the remission rate for bortezomib by itself was something like 30%, which is okay. With ibrutinib, it was about 75%. So when ibrutinib came along, everyone was just using it by itself. I don’t know if there are that many studies. I think a lot of people are always looking for non-injectable clinical trials or drugs, so instead of combining it with an older drug, the thought process was to try it with a new and improved oral drug. That’s kind of what led to the rationale of combining it with this newer ixazomib drug instead of bortezomib.

TARGETED ONCOLOGY: Is ibrutinib being studied in other combinations?

Evens: We can give ibrutinib today in the clinic, but as I mentioned before with the remission rate, it’s still not curative. That’s true for MCL in general – newly diagnosed, not relapsed. MCL is very treatable, but it’s not curable. Whatever treatment you give, you know at some point, the patient is going to relapse. We are in a continual hope of trying to find that magical combination where we can actually find a cure.

TARGETED ONCOLOGY: What other MCL studies are ongoing at Rutgers?

Evens: There’s so many new targeted drugs out there. The other study we have ongoing is a phase II study of a drug called onalespib, a heat shock protein 90 (Hsp90) inhibitor. This is basically a new target. It’s not FDA approved. It has been tested in many patients, but it’s a new target. This is one pathway that is active in MCL, as well as other cancers. The study does not include just MCL. It also includes multiple B-cell lymphomas. We also enrolled diffuse large B-cell to the trial.

TARGETED ONCOLOGY: You mentioned that there is an upcoming study as well. Can you discuss that trial?

Evens: What we want is for every lymphoma subtype to at least have an option for patients who have either relapsed or they are newly diagnosed. There are treatments for every lymphoma, no matter what lymphoma you have. We want to do better for patients where it comes back and we also want to do better for patients that have not yet been treated and are newly diagnosed.

The name of our study is EA4151. This is for newly diagnosed patients. The problem with MCL is that you can use almost anything, and the majority of patients will go into remission. But if you don’t give the right therapy, that remission will only last a few months. It has a very high relapse rate. 

This study doesn’t care what you give to get a patient into remission, a second part to the treatment of a newly diagnosed patient is consolidation. There currently is a lot of debate about whether to do a bone marrow transplant in consolidation for an MCL patient in remission, or should I just give rituximab for 2-3 years, or sometimes longer.

What this study is doing is very smart, because it’s not just randomizing patients to transplant or rituximab. A lot of people tend to think you should do a bone marrow transplant, while other people think you don’t need that, you just need antibody. What this study is doing is using what’s called minimal residual disease (MRD) so that you can analyze rare cells in the blood. In the clinic now, when a patient goes into remission, you know there’s likely disease there, but it’s hard to measure it. There are very sophisticated tests out there that we can’t usually use in the clinic, but this study is going to let us do one of these tests to see if we can see MRD, and then based on whether you see it or not, that will help tell us to randomize to either transplant or rituximab. It’s testing 2 things: can we analyze rare MCL cells in the blood? And after that, does it matter if the patient gets a bone marrow transplant, which many think is the standard of care, or if they just get rituximab? 

This is a national study that’s being conducting at over 100 sites across the United States, and we will be one of them. We will be the only one in New Jersey. The study is already open at a couple sites, but the study at Rutgers is probably about 3 months away, so my hope would be that this summer the study would be open for patients.

TARGETED ONCOLOGY: In the field at large, what areas of research are you particularly excited about?

Evens: One study that recently finished is a study similar to the first one I discussed, basically where they were testing and integrating new drugs into the frontline setting. A standard treatment for MCL is chemotherapy like bendamustine and rituximab, followed by a bone marrow transplant. But do we need to use chemotherapy? Can we use more drugs like ibrutinib, ixazomib, and venetoclax? Can we use these in newly diagnosed?

There are a few studies that have been finished. We don’t have the results yet, and we’re waiting anxiously to see how newly diagnosed patients with MCL do with a chemotherapy-free approach. With chemotherapy free, can we get the same or perhaps better results by using targeted drugs like ibrutinib, lenalidomide (Revlimid), etc and not have to use chemotherapy? The jury is still out.

We are really excited about seeing those results, because you can’t assume. You are hopeful that you don’t have to use chemotherapy, but you do it and sometimes it works a lot worse. You don’t want to assume, because we know with chemotherapy and rituximab, 90%-95% of patients will go into remission. With those studies that have been done and are testing these new drugs, we haven’t seen the results, testing the results in the induction part, but also in the maintenance part. It’s all the different phases of treating MCL, which is looking at different drugs at different phases and trying to find the most effective, safest drug that keeps patients in remission the longest.

We’re really excited that we should have [a trial] available this summer – you hear a lot about immunotherapy, and one of the big immunotherapy things is CAR T-cells. These CAR T-cells are only approved right now for diffuse large B-cell lymphoma and acute leukemia. But there are CAR T-cells being looked at in MCL. We look forward to having that program up and running this summer.

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