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

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

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.

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.

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.