This clinical trial is evaluating whether addition of navtemadlin to ruxolitinib treatment will provide more clinical benefit than ruxolitinib alone for patients with Myelofibrosis who have a suboptimal response to ruxolitinib treatment alone.

Subjects will start by receiving ruxolitinib alone in the run-in period. Those who demostrate a suboptimal response from ruxolitinib alone will then be randomized 2:1 to receive navtemadlin or navtemadlin placebo as add-on treatment to their ongoing ruxolitinib. Randomized means that subjects will be assigned to a group by chance, like a flip of a coin. The study is blinded, meaning the subjects, doctors, central endpoint assessors and sponsor will not know which add on treatment (navtemadlin or navtemadlin placebo) the subject is receiving.

Inclusion Criteria for Ruxolitinib Alone Period:

• Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by the treating physician according to the World Health Organization (WHO) criteria
• High, Intermediate-1, Intermediate-2 risk category International Prognosis System Score (IPSS)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• JAK-inhibitor treatment naive

Exclusion Criteria for Ruxolitinib Alone Period:

• Prior Splenectomy
• Splenic irradiation within 3 months prior to the first dose
• Prior BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors therapy or p53-directed therapy
• Eligible for Bone Marrow Transplant
• Peripheral blood or bone marrow blast count ≥ 10 percent

Inclusion Criteria for Randomized Period:

• PMF, post-PV MF, or post-ET MF that is TP53WT as assessed by central testing
• ECOG performance status of 0 to 2
• Treatment with a stable dose of ruxolitinib
• Suboptimal response to run-in ruxolitinib treatment

Exclusion Criteria for Randomized Period:

• Elevated white blood cell count that doubles (or more) during ruxolitinib treatment and exceeds 50 × 10^9/L
• Peripheral blood or bone marrow blast count ≥ 10 percent

Placebo-controlled