This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.

This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.

Inclusion Criteria:

• Confirmed diagnosis of PMF, post-PV MF or post-ET MF (WHO)
• High, intermediate-2, or intermediate-1 risk Dynamic International Prognostic System (DIPSS)
• Failure of prior treatment with JAK inhibitor
• ECOG ≤ 2

Exclusion Criteria:

• Prior splenectomy
• Splenic irradiation within 3 months prior to randomization
• History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
• History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization
• Prior MDM2 inhibitor therapy or p53-directed therapy
• Prior allogeneic stem-cell transplant or plans for allogeneic stem cell transplant
• History of major organ transplant
• Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0)