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New Phase 3 Clinical Trial for Myelofibrosis Patients

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Published on December 5, 2020

Clinical Trial Offers Promising New Treatment Option for Myelofibrosis

A phase 3 clinical trial studying the use of a new inhibitor for the treatment of myelofibrosis has been announced at the ASH 2020 conference. The MANIFEST 2 Trial builds on the successful MANIFEST trials and is studying the use of a new drug (CPI-0610) as a promising treatment option for myelofibrosis, both on its own and in combination with ruxolitinib (Jakafi).

Learn more about the trial from Dr. John Mascarenhas, MD, Associate Professor of Medicine at Mount Sinai, and Andrew Schorr, Patient Power co-founder and myelofibrosis patient. Together they will discuss the studies that led to the MANIFEST 2 trial, what patients are candidates for the trial and what results have shown so far.

If you are a Myelofibrosis patient interested in participating in a clinical trial, use our online tool to start your search. For other MPNs visit the MPN Research Foundation to find open trials.

This program is sponsored by Constellation Pharmaceuticals. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.


Transcript | New Phase 3 Clinical Trial for Myelofibrosis Patients

Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr in California. Joining us from New York City is a noted MPN and leukemia specialist, Dr. John Mascarenhas. Dr. Mascarenhas is Associate Professor and Director of the Adult Leukemia Program at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Mascarenhas, thanks for being with us.

Dr. Mascarenhas: Thanks for having me.

Andrew Schorr: So, Dr. Mascarenhas, we have the ASH conference, American Society of Hematology, and there is always important data being presented. You presented data that I am very interested in, as someone living with myelofibrosis who gets a single drug to try to relieve symptoms for that, a JAK inhibitor, but I understand you have data on the MANIFEST trial that's combination therapy. So, go ahead and tell us what is the MANIFEST trial, so we can understand his patients and what it could mean to us.

What Is the MANIFEST Clinical Trial?

Dr. Mascarenhas: So, the MANIFEST trial, I think, is a great example of where this field is moving. The field is moving towards combinations of therapies that can be used together that have different mechanisms of action that would hopefully, incur deeper responses, whether it's spleen, symptom, bone marrow fibrosis, blood count changes, or even molecular responses than what we've seen so far with single agents. Really, if you look at oncology across the board, in most cases, most oncologic conditions are treated with combinations of therapy because the responses are better and usually, the progression and durability of those responses are better when you use combinations of therapy.

So, the MANIFEST trial is a trial that is somewhat complex in nature because it really includes different cohorts of patients. So, the initial cohorts of patients were patients who were treated with ruxolitinib (Jakafi) who failed, and failure can mean different things for different patients, and then come off a single agent ruxolitinib and then were treated with a drug called CPI-0610, which is an oral BET inhibitor.

What that really means is a drug that affects transcription or expression of genes. It's a form of epigenetic therapy. You'll hear that term often in oncology. It affects the way genes are transcribed; essentially, that means the way they are expressed. There are a number of genes that are regulated by these BET proteins, including genes that are regulated by a factor called NF kappa B (NF-kB) that when you inhibit this network, you reduce the elaboration of what are called inflammatory cytokines. Those are molecules that promote... are a consequence of the disease and actually, promote aspects of the disease and probably mediate to large part how patients feel, so the symptom burden. By down-regulating these cytokines, you are also probably affecting other aspects of disease beyond symptoms like fibrosis in the bone marrow, which is a hallmark of the disease.

We believe that the combination, particularly of Jakafi, ruxolitinib, plus CPI maybe even more potent in down-regulating genes that are contributing to the pathology of this disease. So, there are many preclinical models, or I should say there are important preclinical models that have been evaluated with these drugs that recapitulate myelofibrosis, and they have really been the basis of why this study went forward because they show that the two drugs work better in combination than a single drug alone. So, the MANIFEST trial tried to capitalize on that. The first cohort of patients were patients who had failed ruxolitinib and would get CPI-0610, this oral drug, for two weeks in a row out of a three-week cycle; so, once a day for 14 days, and then seven days off, and a cycle's 21 days.

They would keep getting this drug. We would assess them for responses and spleen, symptoms and with bone marrows with bone marrow fibrosis. Then there were a cohort of patients that were still on Jakafi or ruxolitinib that were having a suboptimal response, their symptoms were present, their spleen was still large, and the investigator deemed them not fully responsive to ruxolitinib alone. That cohort enjoyed the ability to get CPI added onto ruxolitinib. So that's a combination cohort.

We ultimately included a third cohort of patients who were JAK inhibitor naive. So, these were patients who had not seen ruxolitinib or fedratinib (Inrebic) previously, and they would get the combination upfront as a strategy to start treating the disease earlier on with the two drugs, rather than waiting for the patients to fail or be failing ruxolitinib. In each case, we were looking and stratifying patients, whether they were anemic and transfusion dependent or not. So, for the patients who are transfusion dependent, the goal was to make them transfusion independent. For the patients who are not, the goal was the standard spleen volume reduction.

What is the MANIFEST 2 Clinical Trial?

This study really is a pivotal study in the field right now because it really sets a tone and a paradigm shift to moving beyond the single agent ruxolitinib upfront treatment strategy to combination strategies. The MANIFEST II study will explore this in a randomized phase III study. This is an important study that I think the MF community should watch carefully, whether you're going to participate in it or not, because it sets a tone of comparing ruxolitinib, which has really been the foundation of myelofibrosis treatment for the last decade, ruxolitinib alone, or in combination with a placebo pill versus ruxolitinib plus CPI-0610. This study will hopefully demonstrate superiority of ruxolitinib in combination with CPI, both from the spleen and symptom perspective, but hopefully, also in other parameters that we think are meaningful, for example, anemia improvement, transfusion independence, reduction of bone marrow fibrosis. This is really going to be an exciting and important study that I really do believe will move the field forward.

It's really predicated on the data that we, as a group and many patients contributed to, which showed that if you combine the two drugs in the phase II setting that we just completed, you get a 67% spleen volume reduction rate. What that really means, or what that means to me at least, is if you think back historically from the COMFORT studies and other similar studies of single-agent ruxolitinib, you get response rates of spleen that range between 30% and 40%. And in a third of the patients, you get reduction in bone marrow fibrosis within a six-month period. That, you typically don't see with single-agent ruxolitinib. That really, I think, hits home to the idea that the combinations of the drugs are affecting the disease in a different way, perhaps in a more profound way.

Andrew Schorr: I am really excited as a myelofibrosis patient because while my JAK inhibitor has been working so far, I never know how long, and you're talking about a more powerful and not particularly toxic approach. So that is really terrific. So just to sum up then, Dr. Mascarenhas, combination therapy may prove to be the name of the game. The data you have so far is very promising, and there are patients who are watching who may still consider being in the phase III trial. Correct?

Are Patients Still Able to Join This Trial?

Dr. Mascarenhas: I hope so. I hope so because I think patients often realize that the reason why people like yourself and many other patients are enjoying and benefiting from ruxolitinib today is because over a decade ago, brave patients showed up, many to my center and other contributing centers, and enrolled in the original COMFORT studies and because of their actions, we have a drug. Now, we have two drugs that are commercially approved that have improved the way we treat patients. We're moving into the future and I think that the next approach is really to improve upon that building block.

Andrew Schorr: Dr. Mascarenhas, as people hear about very positive data for the investigational work so far. They say, "Well if the trials are ongoing, how can I be in it? And how do I know if I'll qualify?"

Who Is a Candidate for Participating in MANIFEST 2 Trial?

Dr. Mascarenhas: That's a great question. What I always encourage patients to do when they're out in the community and they're interested in participating in a clinical trial or wondering if they're even eligible for a clinical trial is twofold. One is to discuss it with your hematologist who's taking care of you because sometimes it's very powerful, I think, for a patient to bring up the interest in a clinical trial or to explore options with the hematologists because many docs in the community are not always considering that for each individual patient.

When it's brought up by the patient, I think the concept goes further than a physician introducing the concept or the options with patients. Patients can always go online to If you type in, "myelofibrosis," if you type in, "CPI-0610," you can start to peruse and look at all the different trials that are available, including the MANIFEST study. There are also contacts through the MPN Research Foundation and other patient support groups that usually link patients to specific websites or telephone numbers of where you can identify a clinical site and get a consultation. But essentially, the patient population that is appropriate for this study are patients who have not been treated with ruxolitinib, Jakafi, or fedratinib, Inrebic.

These are patients who have a certain degree of myelofibrosis, which means they have a risk score of intermediate or high-risk disease, and that they have a platelet count of at least 100,000 and have a palpable spleen or a measurable spleen by MRI or CAT scan.

Andrew Schorr: Well, thank you for explaining, really, the powerful data that's come out so far, the opportunity for people to be in a clinical trial and to try to have sort of the way I see it as, a one, two punch against the myelofibrosis, drugs operating differently, as you said, with this new concept for a lot of us, a BET inhibitor added to a JAK inhibitor to really try knock back the myelofibrosis and let us live longer and live better. Dr. John Mascarenhas from Mount Sinai in New York and Tisch School of Medicine, thank you for this data and the work you do and really encouraging us. John, thank you so much for being with us.

Dr. Mascarenhas: Thanks for having me.

Andrew Schorr: I'm Andrew Schorr. Good news, I think, very promising news for myelofibrosis patients as research moves ahead. Remember, knowledge can be the best medicine of all.

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