MANIFEST-2: a global phase 3 trial of pelabresib (CPI-0610) in combination with ruxolitinib in patients with myelofibrosis (MF) who are JAK inhibitor (JAKi) treatment-naïve

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Trial Synopsis

Constellation Pharmaceuticals is conducting a randomized, double-blind, Phase 3 trial in adult patients with myelofibrosis who have not been previously treated with a JAK inhibitor. The purpose of the study is to evaluate the efficacy and safety of pelabresib, an oral BET inhibitor, plus ruxolitinib (a JAK inhibitor) compared with ruxolitinib alone.

Trial status: Recruiting, Phase 3

Study population (N=~310) Prespecified subgroup analyses Treatment arms JAKi-naïve patients with PMF, PPV-MF, or PET-MF and: • Advanced MF requiring therapy • Splenomegaly • Symptomatic disease • See full criteria Patients will be stratified by: • DIPSS risk category (Int-1 vs Int-2 vs High) Pelabresib + ruxolitinib Placebo + ruxolitinib • Platelet count • Spleen volume Double-blind randomization (1:1) JAKi-naïve patients with PMF, PPV-MF, or PET-MF and: • Advanced MF requiring therapy • Splenomegaly • Symptomatic disease • See full criteria Double-blind randomization (1:1) Patients will be stratified by: • DIPSS risk category (Int-1 vs Int-2 vs High) • Platelet count • Spleen volume Treatment arms Pelabresib + ruxolitinib Placebo + ruxolitinib Double-blind randomization (1:1) Study population (N=~310) Prespecified subgroup analyses

Primary endpoint: SVR35 at 24 weeks
Key secondary endpoint: TSS50 by MFSAF v4.0 at 24 weeks
Other secondary endpoints

To learn more or enroll: Contact Us

BET=bromodomain and extra-terminal domain; DIPSS=Dynamic International Prognostic Scoring System; OS=overall survival; PFS=progression-free survival; SVR35=spleen volume reduction of ≥35%; TSS=Total Symptom Score; TSS50=Total Symptom Score improvement of ≥50%; MFSAF=Myelofibrosis Symptom Assessment Form.

What is pelabresib?

Pelabresib (formerly known as CPI-0610) is a novel, orally administered small molecule designed to selectively inhibit the function of BET proteins to decrease the expression of abnormally expressed genes in cancer.

NOTE: Pelabresib is an investigational new drug and not yet approved by any regulatory authority.

The Science Behind
BET Inhibition

Myelofibrosis is an uncommon type of blood cancer that affects the bone marrow and production of blood cells. It is characterized by 4 hallmarks: splenomegaly, inflammation/constitutional symptoms, anemia, and bone marrow fibrosis.

In myelofibrosis, gene signaling pathways that regulate the normal function of bone marrow and myeloid cell differentiation become uncontrolled. This leads to the overproduction of megakaryocytes and inflammatory cytokines, and a decrease in erythrocyte production. Emerging research has shown that bromodomain and extra-terminal domain (BET) proteins are involved in several of these pathways. BET proteins are epigenetic readers and may contribute to the progression of myelofibrosis, as well as other cancers.

The JAK‐STAT (Janus kinase signal transducer and activator of transcription) signaling pathway has been implicated in myelofibrosis and is believed to affect the overproduction of cytokines. Ruxolitinib, the current standard of care in myelofibrosis, targets this pathway and reduces splenomegaly and improves symptoms.

Early data have shown that simultaneous inhibition of BET (to regulate gene transcription) and of JAK-STAT signaling may address disease hallmarks associated with both JAK-independent and JAK-mediated pathways in myelofibrosis.

About Constellation
Pharmaceuticals

Constellation Pharmaceuticals is a clinical-stage biopharmaceutical company. We believe in the power of science to change lives. Utilizing expertise in epigenetics, our mission is to discover and develop novel therapies that address serious unmet medical needs in patients with cancers associated with abnormal gene expression.

We put patients at the center of everything we do, and are dedicated to connecting breakthrough science with new treatments.

What are the eligibility criteria for MANIFEST-2?

Adult patients with a confirmed diagnosis of myelofibrosis (PMF or PPV-MF or PET-MF) in accordance with the 2016 criteria from the World Health Organization (WHO) must meet the following criteria to enroll:

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Never received treatment with a JAK inhibitor for a myeloproliferative neoplasm

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Require therapy for myelofibrosis in the opinion of the investigator and are eligible for treatment with ruxolitinib

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Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

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Spleen volume of ≥450 cm3
by MRI or CT scan

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DIPSS risk category
Intermediate-1 or higher

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Peripheral blood
blast count <5%

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At least 2 measurable symptoms using the Myelofibrosis Symptom Assessment Form (version 4) with a weekly average score of ≥3 and a total weekly score of >10

Where is MANIFEST-2 being conducted?

Trial site locations are continuously being added. Bookmark the ClinicalTrials.gov page below to stay updated on new locations.

Visit ClinicalTrials.gov
Represents global sites as of 11/2020;
subject to change.

How do I enroll patients in MANIFEST-2?

Please contact us for more information on MANIFEST-2, including how to enroll a patient, becoming an investigator, or conducting the MANIFEST-2 trial at your institution.

Contact Constellation

Debbie Johnson,
     Vice President Clinical Operations Debbie.Johnson@constellationpharma.com Daniel Hennessy, PhD,
     Vice President Medical Affairs Daniel.Hennessy@constellationpharma.com
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