What side effects are associated with this type of intervention?

Common treatments for Primary Myelofibrosis (PMF) include JAK inhibitors like ruxolitinib, which can cause side effects such as anemia, thrombocytopenia, and increased risk of infections. BET protein inhibitors, like Pelabresib (CPI-0610), are being studied and may have side effects including gastrointestinal disturbances, fatigue, and potential hematologic toxicities. It is important to discuss with a healthcare provider to understand the specific risks and benefits of each treatment option.

What prior FDA approvals exist?

The FDA has approved several treatments for Primary Myelofibrosis, primarily focusing on Janus kinase (JAK) inhibitors. Ruxolitinib, a JAK1/JAK2 inhibitor, was one of the first approved and remains a cornerstone of PMF treatment. Fedratinib, another JAK2 inhibitor, is also approved for patients with PMF, especially those who are resistant or intolerant to Ruxolitinib. While BET protein inhibitors like Pelabresib (CPI-0610) are still under investigation, these JAK inhibitors represent the current standard of care for managing PMF.

What other types of research exist?

Ruxolitinib, a JAK1/2 inhibitor, remains a promising treatment for Primary Myelofibrosis, especially for patients with significant symptoms and splenomegaly. It has demonstrated a survival advantage in Phase III trials. Another potential alternative is Fedratinib, another JAK2 inhibitor, which has shown efficacy in patients resistant or intolerant to Ruxolitinib. Both of these treatments are viable options for PMF patients considering treatment in 2024.

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Bromodomain and Extra-Terminal Protein Inhibitor

Pelabresib for Myelofibrosis (MANIFEST-2 Trial)

Phase 3

Waitlist Available

Research Sponsored by Constellation Pharmaceuticals

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Confirmed diagnosis of myelofibrosis (primary, post-polycythemia vera, or post essential thrombocythemia)

Prognostic risk-factor score of Intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system

Must not have

Had prior treatment with any JAKi or BET inhibitor for treatment of a myeloproliferative neoplasm

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 24 weeks of treatment

Awards & highlights

Pivotal Trial

Summary

This trial tests a new drug combination of pelabresib and ruxolitinib in patients with myelofibrosis who haven't tried certain treatments before. Pelabresib blocks harmful proteins, and ruxolitinib stops harmful signals to see if this combination works better.

Who is the study for?

This trial is for adults with myelofibrosis, including those who developed it from polycythemia vera or essential thrombocythemia. Participants must have certain symptoms and spleen enlargement, be in a specific risk category, and have good organ function. They can't join if they've had their spleen removed recently or used JAKi/BET inhibitors before.

What is being tested?

The study tests Pelabresib (a BET protein inhibitor) combined with Ruxolitinib versus a placebo with Ruxolitinib in patients new to JAK inhibitor treatments. It's randomized and blinded, meaning participants are assigned by chance to either the test drug or placebo without knowing which one they receive.

What are the potential side effects?

Potential side effects of Pelabresib include gastrointestinal issues like nausea and vomiting, fatigue, muscle pain, anemia (low red blood cell count), potential liver enzyme changes indicating liver stress, and possible respiratory problems.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with myelofibrosis.

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My condition is rated Intermediate-1 or higher on the DIPSS scale.

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I can take care of myself and am up and about more than half of my waking hours.

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I've had symptoms scoring 3 or more on average, or a total score of 10 or more, in the last week.

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My spleen is enlarged, measuring 450 cm^3 or more.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I have been treated with JAKi or BET inhibitors for a blood disorder.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 24 weeks of treatment

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~24 weeks of treatment

This trial's timeline: 3 weeks for screening, Varies for treatment, and 24 weeks of treatment for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of Participants With Splenic Response by Central Reads at Week 24

Secondary study objectives

Number of Participants With TSS50 Response at Week 24

Total Symptom Score Absolute Change From Baseline to Week 24

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Pelabresib + ruxolitinibExperimental Treatment2 Interventions

Pelabresib monohydrate tablets + ruxolitinib phosphate tablets

Group II: Placebo + ruxolitinibActive Control2 Interventions

Matching placebo tablets + ruxolitinib phosphate tablets

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Pelabresib

2021

Completed Phase 1

~40

Ruxolitinib

2018

Completed Phase 3

~1170

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Primary Myelofibrosis (PMF) treatments often target the underlying molecular abnormalities and symptomatic burden of the disease. Ruxolitinib, a Janus kinase (JAK) inhibitor, reduces splenomegaly and alleviates symptoms by inhibiting the JAK-STAT pathway, which is often hyperactive in PMF. Hydroxyurea, a cytoreductive agent, helps control elevated blood counts and reduce spleen size. Pelabresib (CPI-0610), a BET protein inhibitor, works by modulating gene expression to decrease megakaryocytic progenitors and normalize CD4+ T cells, addressing the myeloid-lymphoid imbalance seen in PMF. These mechanisms are crucial as they not only alleviate symptoms but also potentially modify the disease course, improving quality of life and outcomes for PMF patients.

MPN-238 Single-Cell RNA Profiling of Myelofibrosis Patients Reveals Pelabresib-Induced Decrease of Megakaryocytic Progenitors and Normalization of CD4+ T Cells in Peripheral Blood.