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Phase 3RecruitingInterventionalNCT07357727

A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF) (MANIFEST-3)

A Phase 3, Randomized, Double-blind, Active-control Study of Pelabresib (DAK539) and Ruxolitinib vs. Placebo and Ruxolitinib in Adult Patients With Myelofibrosis Who Are JAK Inhibitor Naive

  • Primary Myelofibrosis (PMF)
  • Post-polycythemia Vera Myelofibrosis (PPV-MF)
  • Post-essential Thrombocythemia Myelofibrosis (PET-MF)
I want to take partRefer a patient5 sites in India · 110 worldwide

At a glance

Phase
Phase 3
Study type
Interventional
Sponsor
Novartis Pharmaceuticals
Enrolment target
460
Started
27 May 2026
Main results due (estimated)
17 May 2028
Study ends (estimated)
27 December 2030
Allocation
Randomized
Design
Parallel
Purpose
Treatment
Masking
Quadruple (participant, care provider, investigator, outcomes assessor)
Sites
110 · 5 in India
First posted
22 January 2026
Registry updated
1 October 2026

Can you take part?

  • Aged 18 years and over.
  • Open to any sex.
  • You need the condition being studied. Healthy volunteers are not accepted.

Age groups: adult, older adult.

These are the headline rules. Every study has a longer list, and whether you are eligible is decided by the research team at the site, never by this page.

Read the full eligibility criteria
Key Inclusion Criteria:

* Participants have diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF) according to the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias 2022
* DIPSS risk category of intermediate-1, intermediate-2 or high-risk
* Spleen volume ≥ 450 cm3 by CT or MRI scan (local read sufficient if no central read available)
* Have an average TSS of ≥15 within 7 days prior to randomization, using MFSAF v. 4.0 (at least 4 out of 7 TSS assessments required for average calculation)
* Participants with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* Blasts \<5% in peripheral blood. Assessment of blasts in peripheral blood is mandatory at screening
* Platelet count ≥ 100 x 10\^9/L in the absence of growth factors or transfusions for the previous 4 weeks

Key Exclusion Criteria:

* Prior splenectomy at any time or splenic irradiation in the previous 6 months
* Prior hematopoietic cell transplant or participant anticipated to receive a hematopoietic cell transplant within 24 weeks from the date of randomization
* Blasts ≥ 5% in bone marrow if results available at screening or history of accelerated phase (AP) or leukemic transformation
* History of a malignancy (other than MF, PPV-MF or PET-MF) in the past 3 years in need of systemic treatment
* Received any approved or investigational agent other than hydroxyurea or anagrelide for the treatment of MF within 14 days of first dose of study treatment or within 5 half-lives of the approved or investigational agent, whichever is longer
* Prior treatment with any JAK inhibitor or Bromodomain and extraterminal domain (BET) inhibitor

Other protocol-defined inclusion/exclusion criteria may apply.

What this study is about

In the sponsor’s own words, from the registry.

The purpose of this trial is to evaluate whether treatment with pelabresib in combination with ruxolitinib leads to improved clinical outcomes compared to ruxolitinib alone in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF) who have not previously received Janus kinase (JAK) inhibitor therapy.

Read the detailed description

The study for each participant is composed of several distinct periods: a screening period, a study treatment period, and a post-treatment follow-up phase.

1. Screening Period:

The screening period lasts for up to 28 days prior to Cycle 1 Day 1, which marks the beginning of treatment. During this time, the participant's eligibility for the study is confirmed, informed consent is obtained, and all required baseline assessments are completed. 2. Treatment Period:

The treatment period begins on Cycle 1 Day 1, which is the point of randomization and the start of study treatment. This period continues until the participant permanently discontinues study treatment, which may occur due to disease progression, unacceptable toxicity, participant withdrawal, or other reasons specified in the protocol. Throughout this period, participants receive study drugs in 21-day cycles, with pelabresib or placebo administered for 14 days and ruxolitinib given continuously. Regular site visits and assessments are conducted according to the Schedule of Activities. 3. Safety Follow-up Period:

The safety follow-up period extends for 30 days (with a window of plus or minus 3 days) after the participant receives their last dose of pelabresib or placebo. During this period, participants are monitored for any late-onset adverse events or safety concerns that may arise after discontinuing the study treatment. 4. Efficacy Follow-up Period:

Following the safety follow-up, efficacy follow-up visits are scheduled every 12 weeks for participants who have not shown evidence of disease progression, meaning there is no documented progression of splenomegaly or leukemic transformation and no new therapy for myelofibrosis has been started. The purpose of this follow-up is to continue monitoring efficacy endpoints, such as spleen imaging, laboratory assessments, and bone marrow biopsies, until either disease progression occurs or a new therapy is initiated. 5. Survival Follow-up Period:

Once a participant enters the survival follow-up phase, follow-up visits are conducted every 12 weeks and may be performed remotely. This phase applies to participants who have experienced documented disease progression or have started a new therapy for myelofibrosis. The aim of survival follow-up is to monitor overall survival and to collect ongoing data regarding disease status and any subsequent therapies the participant may receive.

Keywords: Pelabresib (DAK539) · Ruxolitinib · Adult participants · Myelofibrosis (MF)

What participants receive

  • Experimental

    Arm 1: Pelabresib + Ruxolitinib

    Participants in this arm receive pelabresib (DAK539) orally once daily for 14 days of each 21-day cycle, in combination with ruxolitinib, which is taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.

    Drug: Pelabresib · Drug: Ruxolitinib

  • Placebo comparator

    Arm 2: Placebo + Ruxolitinib

    Participants in this arm receive a matching placebo orally once daily for 14 days of each 21-day cycle, together with ruxolitinib, which is also taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.

    Drug: Ruxolitinib · Drug: Placebo

Interventions

  • PelabresibDrug

    Also known as DAK539

    Pelabresib monohydrate tablets

  • RuxolitinibDrug

    Also known as INC424

    Ruxolitinib phosphate tablets

  • PlaceboDrug

    Matches pelabresib

What the study measures

Primary outcomes

  1. Number of Participants with Splenic Response (SVR35) by Central Radiology Reads at Week 24 in participants with baseline total symptom score (TSS) ≥ 25

    Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 25.

    Time frame: Week 24

  2. Absolute change from baseline in total symptom score (TSS) at Week 24 in participants with baseline TSS ≥ 25

    Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 25.

    Time frame: Baseline, Week 24

  3. Number of Participants with Splenic Response (SVR35) by Central Radiology Reads at Week 24 in participants with baseline TSS ≥ 15

    Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 15.

    Time frame: Week 24

  4. Absolute change from baseline in total symptom score (TSS) at Week 24 in participants with baseline TSS ≥ 15

    Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 15.

    Time frame: Baseline, Week 24

Secondary outcomes

  1. Number of Participants with Splenic Response (SVR35) by Central Radiology Reads over time

    Spleen Response (SVR35) over time is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 12, Week 36, Week 48 and thereafter, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review.

    Time frame: Week 12, Week 36, Week 48 and every 12 weeks thereafter till End of Study (an average of 3 years)

  2. Absolute change from baseline and percentage change from baseline in spleen volume over time

    Absolute and percentage change from baseline in spleen volume over time will be summarized using descriptive summary statistics

    Time frame: Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years)

  3. Time to first SVR35 response

    Time to first SVR35 response defined as the time from date of randomization to the date of first SVR35 response as measured by MRI (or CT scan) will be summarized by treatment arm.

    Time frame: From date of randomization to the date of first SVR35 response, assessed up to approximately 3 years

  4. Duration of first SVR35 response

    Duration of first SVR35 response defined as the time from first SVR35 response to loss of response for any participant who reaches SVR35 at any time.

    Time frame: From first SVR35 response to loss of response, assessed up to approximately 3 years

  5. Number of Participants with TSS50 response at Week 24

    Symptom response defined as achieving ≥ 50% reduction in total symptom score (TSS50) from baseline to Week 24 as measured by the MFSAF v4.0

    Time frame: Week 24

  6. Number of Participants with TSS50 response over time

    Symptom response defined as achieving ≥ 50% reduction in total symptom score (TSS50) from baseline to Week 12, Week 36, Week 48 and thereafter as measured by the MFSAF v4.0

    Time frame: Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years)

  7. Absolute and percentage change from baseline in TSS over time

    Absolute change from baseline and percentage change from baseline in TSS over time

    Time frame: Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years)

  8. Time to first TSS50 response

    Time to first TSS50 response defined as the time from date of randomization to the date of first TSS50 response as measured by the MFSAF v4.0.

    Time frame: From date of randomization till date of first TSS50 response, assessed up to approximately 3 years

  9. Duration of TSS50 response

    Duration of TSS50 response defined as the time from first TSS50 response to loss of response for any participant who reaches TSS50 at any time.

    Time frame: From first TSS50 response to loss of response, assessed up to approximately 3 years

  10. Dual Response (SVR35 + TSS50)

    Dual response is defined as achieving both ≥ 35% reduction in spleen volume (SVR35) and ≥ 50% reduction in total symptom score (TSS50) from baseline to Week 12, 24, 36, 48 and every 12 weeks thereafter, with SVR measured by MRI (or CT scan) and assessed by central radiology read and TSS measured by MFSAF v4.0.

    Time frame: Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years)

  11. Hemoglobin response

    Hemoglobin response defined as a ≥1.5 g/dL average increase in hemoglobin from baseline in any 12-week mean hemoglobin concentration.

    Time frame: 12 consecutive weeks (rolling window) up to 7 days following last dose of pelabresib/placebo

  12. Change from baseline in hemoglobin over time

    Change from baseline in hemoglobin over time will be summarized using descriptive summary statistics.

    Time frame: Up to 7 days following last dose of pelabresib/placebo

  13. Anemia response over time

    Anemia response (major response, minor response, stable anemia, progressive anemia) as per proposed 2024 IWG-ELN criteria in participants with transfusion dependent and non-transfusion dependent anemia (Tefferi et al 2024).

    Time frame: Up to 7 days following last dose of pelabresib/placebo

  14. Overall survival (OS)

    Overall survival (OS) defined as the time from date of randomization to date of death due to any cause.

    Time frame: From date of randomization till date of death due to any cause, assessed up to approximately 3 years

  15. Progression-free survival (PFS)

    Progression-free survival (PFS) defined as the time from date of randomization to date of documented disease progression, or death due to any cause whichever comes first.

    Time frame: From date of randomization till date of documented disease progression, or death due to any cause whichever comes first, assessed up to approximately 3 years

  16. Leukemia-free survival (LFS)

    Leukemia-free survival (LFS) is defined as the time from date of randomization to date of leukemic transformation, or death due to any cause whichever comes first.

    Time frame: From date of randomization till date of leukemic transformation, or death due to any cause whichever comes first, assessed up to approximately 3 years

  17. Exposure-Adjusted Incidence Rate (EAIR) of Participants with Leukemic Transformation

    The EAIR of participants with leukemic transformation is the rate at which this event occurs, adjusted for the actual time participants were exposed to the study drug(s).

    Time frame: Throughout study completion (an average of 3 years)

  18. Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

    Time frame: Up to 30 days following last dose of pelabresib/placebo

  19. Pelabresib plasma concentrations

    Blood samples for pelabresib pharmacokinetics (PK) will be obtained and evaluated in all participants at all dose levels and summarized using descriptive statistics.

    Time frame: Cycle 1: Day 1 (0/Pre-dose and 0.5 post dose), Day 7 (0/Pre-dose), Day 14 (0/Pre-dose, 2, and 5 hours post-dose). 1 cycle = 21 days.

  20. Maximum observed plasma Concentration (Cmax) of pelabresib in participants enrolled in China and Japan

    Venous whole blood samples will be collected for pharmacokinetic characterization in a subset of participants enrolled in China and Japan. Cmax will be listed and summarized using descriptive statistics.

    Time frame: Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.

  21. Time to Maximum observed plasma Concentration (Tmax) of pelabresib in participants enrolled in China and Japan

    Venous whole blood samples will be collected for pharmacokinetic characterization in a subset of participants enrolled in China and Japan. Tmax will be listed and summarized using descriptive statistics.

    Time frame: Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.

  22. Area Under the Concentration-Time Curve over a dosing interval (AUCtau) of pelabresib in participants enrolled in China and Japan

    Venous whole blood samples will be collected for pharmacokinetic characterization in a subset of participants enrolled in China and Japan. AUCtau will be listed and summarized using descriptive statistics.

    Time frame: Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.

  23. Change from baseline over time in fatigue as measured by PROMIS SF v1.0 Fatigue 7a

    The PROMIS Short Form version 1.0 Fatigue 7a is a seven-question survey that measures how much fatigue has affected a person over the past week. Each question is rated from "Never" to "Always" on a five-point scale. The total score is converted to a standardized score, where the average is 50 and the standard deviation is 10. A lower score means less fatigue and minimal impact on daily life, while a higher score indicates more severe fatigue and greater disruption of daily activities.

    Time frame: Baseline, once per week from Cycles 1 to 9 (each cycle is 21 days), day 1 of every odd cycle thereafter, within 7 days of last dose of pelabresib/placebo and at 12 weeks following last dose of pelabresib/placebo

  24. Change from baseline over time in overall QOL and functional scales as measured by the EORTC QLQ-C30

    The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) measures overall quality of life and key functional areas in people with cancer, including physical, role, emotional, cognitive, and social functioning. Items are rated from 1 (not at all) to 4 (very much), except for the global quality of life scale, which uses a 1 to 7 scale. Scores are converted to a 0 to 100 scale. Higher scores indicate better functioning and quality of life, while lower scores reflect poorer functioning and well-being.

    Time frame: Baseline, day 1 of every cycle from Cycle 1 to 9 (each cycle is 21 days), day 1 of every odd cycle thereafter, within 7 days of last dose of pelabresib/placebo and at 12 weeks following last dose of pelabresib/placebo

Who is running it

Lead sponsor
Novartis Pharmaceuticals
Sponsor type
Industry
Responsible party
The sponsor
Organisation
Novartis
Data monitoring committee
Yes
US FDA-regulated drug
Yes
US FDA-regulated device
No
Sponsor's study ID
CDAK539A12303
Other IDs
2025-523555-66-00, 2025

  • Novartis Pharmaceuticals

    Study director

    Novartis Pharmaceuticals

Study sites(110)

  • Novartis Investigative Site

    Aurangabad, Maharashtra, India

    Recruiting

  • Novartis Investigative Site

    Pune, Maharashtra, India

    Recruiting

  • Novartis Investigative Site

    Rishikesh, Uttarakhand, India

    Recruiting

  • Novartis Investigative Site

    Kolkata, West Bengal, India

    Recruiting

  • Novartis Investigative Site

    Delhi, India

    Recruiting

  • Yale University School Of Medicine

    New Haven, Connecticut, United States

    Recruiting

  • Florida Cancer Specialist South Reg

    Fort Myers, Florida, United States

    Recruiting

  • The Anderson Family Cancer Institute

    Jupiter, Florida, United States

    Recruiting

  • Miami NS Ins Baptist Health S FL

    Miami, Florida, United States

    Recruiting

  • Florida Cancer Specialists-North

    St. Petersburg, Florida, United States

    Recruiting

  • Florida Cancer Specialists East

    Stuart, Florida, United States

    Recruiting

  • Winship Cancer Institute of Emory University

    Atlanta, Georgia, United States

    Recruiting

  • Franciscan Health Indianapolis

    Indianapolis, Indiana, United States

    Recruiting

  • American Oncology Partners PA Center for Cancer and Blood Disorders

    Bethesda, Maryland, United States

    Recruiting

  • Summit Medical Group Oncology

    Berkeley Heights, New Jersey, United States

    Recruiting

  • New York Oncology Hematology P C

    Albany, New York, United States

    Recruiting

  • The Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, United States

    Recruiting

  • Texas Oncology PA Dallas Presbyterian Hospital

    Dallas, Texas, United States

    Recruiting

  • MD Anderson Cancer Center

    Houston, Texas, United States

    Recruiting

  • SCRI Texas Oncology Northeast Texas

    Tyler, Texas, United States

    Recruiting

  • Fred Hutch Cancer Research

    Seattle, Washington, United States

    Recruiting

  • Novartis Investigative Site

    Buenos Aires, Buenos Aires F.D., Argentina

    Recruiting

  • Novartis Investigative Site

    CABA, Argentina

    Recruiting

  • Novartis Investigative Site

    Capital Federal, Argentina

    Recruiting

  • Novartis Investigative Site

    Córdoba, Argentina

    Recruiting

  • Novartis Investigative Site

    Adelaide, South Australia, Australia

    Recruiting

  • Novartis Investigative Site

    Clayton, Victoria, Australia

    Recruiting

  • Novartis Investigative Site

    Sankt Pölten, Austria

    Recruiting

  • Novartis Investigative Site

    Goiânia, Goiás, Brazil

    Recruiting

  • Novartis Investigative Site

    Florianópolis, Santa Catarina, Brazil

    Recruiting

  • Novartis Investigative Site

    Barretos, São Paulo, Brazil

    Recruiting

  • Novartis Investigative Site

    Hefei, Anhui, China

    Recruiting

  • Novartis Investigative Site

    Guangzhou, Guangdong, China

    Recruiting

  • Novartis Investigative Site

    Guangzhou, Guangdong, China

    Recruiting

  • Novartis Investigative Site

    Wuhan, Hubei, China

    Recruiting

  • Novartis Investigative Site

    Wuhan, Hubei, China

    Recruiting

  • Novartis Investigative Site

    Nanjing, Jiangsu, China

    Recruiting

  • Novartis Investigative Site

    Nantong, Jiangsu, China

    Recruiting

  • Novartis Investigative Site

    Nanchang, Jiangxi, China

    Recruiting

  • Novartis Investigative Site

    Changchun, Jilin, China

    Recruiting

Showing 40 of 110 sites, filter to narrow it down. 110 of 110 on this study are recruiting right now, and 5 are in India. A site can stop enrolling while the study as a whole is still open.

References and data sharing

Participant data shared
Yes

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Source: ClinicalTrials.gov record NCT07357727, status verified September 2026. Trialion does not run this study, is not paid to refer anyone to it, and cannot enrol you. Eligibility is always decided by the research team at the site.

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A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF) | Trialion